{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T02:06:28Z","timestamp":1792548388905,"version":"4.5.0"},"reference-count":209,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,3,28]],"date-time":"2021-03-28T00:00:00Z","timestamp":1616889600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Despite recent groundbreaking advances in the treatment of cutaneous melanoma, it remains one of the most treatment-resistant malignancies. Due to resistance to conventional chemotherapy, the therapeutic focus has shifted away from aiming at melanoma genome stability in favor of molecularly targeted therapies. Inhibitors of the RAS\/RAF\/MEK\/ERK (MAPK) pathway significantly slow disease progression. However, long-term clinical benefit is rare due to rapid development of drug resistance. In contrast, immune checkpoint inhibitors provide exceptionally durable responses, but only in a limited number of patients. It has been increasingly recognized that melanoma cells rely on efficient DNA repair for survival upon drug treatment, and that genome instability increases the efficacy of both MAPK inhibitors and immunotherapy. In this review, we discuss recent developments in the field of melanoma research which indicate that targeting genome stability of melanoma cells may serve as a powerful strategy to maximize the efficacy of currently available therapeutics.<\/jats:p>","DOI":"10.3390\/ijms22073485","type":"journal-article","created":{"date-parts":[[2021,3,28]],"date-time":"2021-03-28T22:09:01Z","timestamp":1616969341000},"page":"3485","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Targeting Genome Stability in Melanoma\u2014A New Approach to an Old Field"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2575-121X","authenticated-orcid":false,"given":"Marta","family":"Osrodek","sequence":"first","affiliation":[{"name":"Department of Molecular Biology of Cancer, Medical University of Lodz, 92-215 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2251-8647","authenticated-orcid":false,"given":"Michal","family":"Wozniak","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology of Cancer, Medical University of Lodz, 92-215 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1038\/nrc.2015.2","article-title":"DNA damage and the balance between survival and death in cancer biology","volume":"16","author":"Roos","year":"2016","journal-title":"Nat. Rev. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1002\/em.22087","article-title":"Mechanisms of DNA damage, repair, and mutagenesis","volume":"58","author":"Chatterjee","year":"2017","journal-title":"Environ. Mol. Mutagen."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"a012575","DOI":"10.1101\/cshperspect.a012575","article-title":"DNA repair by reversal of DNA damage","volume":"5","author":"Yi","year":"2013","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1038\/cr.2007.115","article-title":"Mechanisms and functions of DNA mismatch repair","volume":"18","author":"Li","year":"2008","journal-title":"Cell Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1007\/s00018-009-8736-z","article-title":"DNA repair in mammalian cells: Base excision repair: The long and short of it","volume":"66","author":"Robertson","year":"2009","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1038\/nrm3822","article-title":"Understanding nucleotide excision repair and its roles in cancer and ageing","volume":"15","author":"Marteijn","year":"2014","journal-title":"Nat. Rev. Mol. Cell. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"10524","DOI":"10.1074\/jbc.TM118.000372","article-title":"Homologous recombination and the repair of DNA double-strand breaks","volume":"293","author":"Wright","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_8","first-page":"130","article-title":"DNA double strand break repair via non-homologous end-joining","volume":"2","author":"Davis","year":"2013","journal-title":"Transl. Cancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1146\/annurev-biophys-051013-022737","article-title":"The Fanconi anemia DNA repair pathway: Structural and functional insights into a complex disorder","volume":"43","author":"Walden","year":"2014","journal-title":"Annu. Rev. Biophys."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1038\/nature01408","article-title":"DNA damage and repair","volume":"421","author":"Friedberg","year":"2003","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1038\/nrn2559","article-title":"DNA repair deficiency and neurological disease","volume":"10","author":"McKinnon","year":"2009","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.ajhg.2019.06.005","article-title":"DNA Damage and Associated DNA Repair Defects in Disease and Premature Aging","volume":"105","author":"Tiwari","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1007\/s11912-018-0732-8","article-title":"The World of Melanoma: Epidemiologic, Genetic, and Anatomic Differences of Melanoma across the Globe","volume":"20","author":"Dimitriou","year":"2018","journal-title":"Curr. Oncol. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21590","article-title":"Cancer statistics, 2020","volume":"70","author":"Siegel","year":"2020","journal-title":"CA Cancer J. Clin."},{"key":"ref_15","unstructured":"(2021, February 10). American Cancer Society. Available online: https:\/\/www.cancer.org\/cancer\/melanoma-skin-cancer.html."},{"key":"ref_16","unstructured":"Cancer Genome Atlas Network (2015). Genomic Classification of Cutaneous Melanoma. Cell, 161, 1681\u20131696."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2665","DOI":"10.1038\/s41467-018-05063-1","article-title":"Patterns of genomic evolution in advanced melanoma","volume":"10","author":"Birkeland","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1007\/s10555-015-9586-9","article-title":"The challenge of targeting metastasis","volume":"34","author":"Fidler","year":"2015","journal-title":"Cancer Metastasis Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1038\/nature25432","article-title":"Chromosomal instability drives metastasis through a cytosolic DNA response","volume":"553","author":"Bakhoum","year":"2018","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1038\/nature09460","article-title":"The patterns and dynamics of genomic instability in metastatic pancreatic cancer","volume":"467","author":"Campbell","year":"2010","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1038\/nature09515","article-title":"Distant metastasis occurs late during the genetic evolution of pancreatic cancer","volume":"467","author":"Yachida","year":"2010","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1038\/s41586-019-1056-z","article-title":"Genomic characterization of metastatic breast cancers","volume":"569","author":"Bertucci","year":"2019","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.ccell.2017.07.005","article-title":"Genomic Evolution of Breast Cancer Metastasis and Relapse","volume":"32","author":"Yates","year":"2017","journal-title":"Cancer Cell."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2109","DOI":"10.1056\/NEJMoa1616288","article-title":"Tracking the Evolution of Non-Small-Cell Lung Cancer","volume":"376","author":"Wilson","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.cell.2018.03.057","article-title":"Tracking Cancer Evolution Reveals Constrained Routes to Metastases: TRACERx Renal","volume":"173","author":"Turajlic","year":"2018","journal-title":"Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e92688","DOI":"10.1172\/jci.insight.92688","article-title":"Genomic landscape and evolution of metastatic chromophobe renal cell carcinoma","volume":"2","author":"Casuscelli","year":"2017","journal-title":"JCI Insight."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.1038\/s41588-019-0507-7","article-title":"The genomic landscape of metastatic breast cancer highlights changes in mutation and signature frequencies","volume":"51","author":"Angus","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/s13000-020-00971-7","article-title":"High tumor mutation burden is associated with DNA damage repair gene mutation in breast carcinomas","volume":"15","author":"Mei","year":"2020","journal-title":"Diagn. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1002\/path.4230","article-title":"Distinct evolutionary trajectories of primary high-grade serous ovarian cancers revealed through spatial mutational profiling","volume":"231","author":"Bashashati","year":"2013","journal-title":"J. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1016\/j.cell.2018.06.039","article-title":"Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer","volume":"174","author":"Quigley","year":"2018","journal-title":"Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.annonc.2019.11.010","article-title":"Prevalence and mutational determinants of high tumor mutation burden in breast cancer","volume":"31","author":"Jain","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1038\/nature12213","article-title":"Mutational heterogeneity in cancer and the search for new cancer-associated genes","volume":"499","author":"Lawrence","year":"2013","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/s41419-020-2702-y","article-title":"Targeting Rad51 as a strategy for the treatment of melanoma cells resistant to MAPK pathway inhibition","volume":"11","author":"Makino","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/sj.onc.1210700","article-title":"High expression of DNA repair pathways is associated with metastasis in melanoma patients","volume":"27","author":"Kauffmann","year":"2008","journal-title":"Oncogene"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1016\/S0140-6736(15)60898-4","article-title":"Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: A multicentre, double-blind, phase 3 randomised controlled trial","volume":"386","author":"Long","year":"2015","journal-title":"Lancet"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1056\/NEJMoa1412690","article-title":"Improved overall survival in melanoma with combined dabrafenib and trametinib","volume":"372","author":"Robert","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1038\/nrclinonc.2017.43","article-title":"Targeted agents and immunotherapies: Optimizing outcomes in melanoma","volume":"14","author":"Luke","year":"2017","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1200\/JCO.2017.74.1025","article-title":"Long-Term Outcomes in Patients With BRAF V600-Mutant Metastatic Melanoma Who Received Dabrafenib Combined With Trametinib","volume":"36","author":"Long","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1158\/2159-8290.CD-17-0682","article-title":"Exploiting Drug Addiction Mechanisms to Select against MAPKi-Resistant Melanoma","volume":"8","author":"Hong","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1038\/s41419-018-0952-8","article-title":"Melanoma cells resistant towards MAPK inhibitors exhibit reduced TAp73 expression mediating enhanced sensitivity to platinum-based drugs","volume":"9","author":"Makino","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1158\/2159-8290.CD-18-0879","article-title":"MAPK Pathway Suppression Unmasks Latent DNA Repair Defects and Confers a Chemical Synthetic Vulnerability in BRAF-, NRAS-, and NF1-Mutant Melanomas","volume":"9","author":"Maertens","year":"2019","journal-title":"Cancer Discov."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"7231","DOI":"10.2147\/CMAR.S263767","article-title":"Insulin Reduces the Efficacy of Vemurafenib and Trametinib in Melanoma Cells","volume":"12","author":"Osrodek","year":"2020","journal-title":"Cancer Manag. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1593\/tlo.12280","article-title":"A systemic complete response of metastatic melanoma to local radiation and immunotherapy","volume":"5","author":"Hiniker","year":"2012","journal-title":"Transl. Oncol."},{"key":"ref_44","first-page":"e417","article-title":"High-Dose Radiation as a Dramatic, Immunological Primer in Locally Advanced Melanoma","volume":"7","author":"Mohiuddin","year":"2015","journal-title":"Cureus"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1158\/2326-6066.CIR-16-0223","article-title":"Metastatic Melanoma Patient Had a Complete Response with Clonal Expansion after Whole Brain Radiation and PD-1 Blockade","volume":"5","author":"Haymaker","year":"2017","journal-title":"Cancer Immunol. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1016\/j.ijrobp.2016.07.005","article-title":"A Prospective Clinical Trial Combining Radiation Therapy With Systemic Immunotherapy in Metastatic Melanoma","volume":"96","author":"Hiniker","year":"2016","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.det.2019.05.001","article-title":"Systemic Therapies for Advanced Melanoma","volume":"37","author":"Bomar","year":"2019","journal-title":"Dermatol. Clin."},{"key":"ref_48","unstructured":"(2021, February 25). National Cancer Institute, Available online: https:\/\/www.cancer.gov\/types\/skin\/patient\/melanoma-treatment-pdq."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/cncr.22427","article-title":"Chemotherapy for metastatic melanoma: Time for a change?","volume":"109","author":"Gogas","year":"2007","journal-title":"Cancer"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1007\/978-3-319-22539-5_8","article-title":"Chemotherapy for Melanoma","volume":"167","author":"Wilson","year":"2016","journal-title":"Cancer Treat. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1200\/JCO.2000.18.1.158","article-title":"Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma","volume":"18","author":"Middleton","year":"2000","journal-title":"J. Clin. Oncol."},{"key":"ref_52","first-page":"3801","article-title":"Sensitization of pancreatic tumor xenografts to carmustine and temozolomide by inactivation of their O6-Methylguanine-DNA methyltransferase with O6-benzylguanine or O6-benzyl-2\u2019-deoxyguanosine","volume":"9","author":"Kokkinakis","year":"2003","journal-title":"Clin. Cancer Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1093\/jjco\/hym132","article-title":"Prognostic significance of O6-methylguanine-DNA methyltransferase protein expression in patients with recurrent glioblastoma treated with temozolomide","volume":"37","author":"Nagane","year":"2007","journal-title":"Jpn. J. Clin. Oncol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1215\/15228517-2008-090","article-title":"Induction of MGMT expression is associated with temozolomide resistance in glioblastoma xenografts","volume":"11","author":"Kitange","year":"2009","journal-title":"Neuro-Oncology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2540","DOI":"10.1200\/JCO.2007.10.8217","article-title":"Randomized trial of the combination of lomeguatrib and temozolomide compared with temozolomide alone in chemotherapy naive patients with metastatic cutaneous melanoma","volume":"25","author":"Ranson","year":"2007","journal-title":"J. Clin. Oncol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1825","DOI":"10.1016\/j.ejca.2004.04.030","article-title":"Re-evaluating the role of dacarbazine in metastatic melanoma: What have we learned in 30 years?","volume":"40","author":"Eggermont","year":"2004","journal-title":"Eur. J. Cancer"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.clindermatol.2012.08.016","article-title":"Chemotherapy in the management of advanced cutaneous malignant melanoma","volume":"31","author":"Luke","year":"2013","journal-title":"Clin. Dermatol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/S1470-2045(10)70288-6","article-title":"Two different durations of adjuvant therapy with intermediate-dose interferon alfa-2b in patients with high-risk melanoma (Nordic IFN trial): A randomised phase 3 trial","volume":"12","author":"Hansson","year":"2011","journal-title":"Lancet Oncol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1093\/annonc\/mdn001","article-title":"Adjuvant low-dose interferon \u03b12a with or without dacarbazine compared with surgery alone: A prospective-randomized phase III DeCOG trial in melanoma patients with regional lymph node metastasis","volume":"19","author":"Garbe","year":"2008","journal-title":"Ann. Oncol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1056\/NEJM199208203270803","article-title":"Treatment of metastatic malignant melanoma with dacarbazine plus tamoxifen","volume":"327","author":"Cocconi","year":"1992","journal-title":"N. Engl. J. Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1743","DOI":"10.1200\/JCO.1998.16.5.1743","article-title":"Phase III trial of dacarbazine versus dacarbazine with interferon alpha-2b versus dacarbazine with tamoxifen versus dacarbazine with interferon alpha-2b and tamoxifen in patients with metastatic malignant melanoma: An Eastern Cooperative Oncology Group study","volume":"16","author":"Falkson","year":"1998","journal-title":"J. Clin. Oncol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"9435389","DOI":"10.1155\/2019\/9435389","article-title":"Radiotherapy for Melanoma: More than DNA Damage","volume":"2019","author":"Rogers","year":"2019","journal-title":"Dermatol. Res. Pract."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1046\/j.1365-2133.2002.04750.x","article-title":"A retrospective study of 150 patients with lentigo maligna and lentigo maligna melanoma and the efficacy of radiotherapy using Grenz or soft X-rays","volume":"146","author":"Farshad","year":"2002","journal-title":"Br. J. Dermatol."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Savoia, P., Fava, P., Casoni, F., and Cremona, O. (2019). Targeting the ERK Signaling Pathway in Melanoma. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20061483"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2507","DOI":"10.1056\/NEJMoa1103782","article-title":"Improved survival with vemurafenib in melanoma with BRAF V600E mutation","volume":"364","author":"Chapman","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1694","DOI":"10.1056\/NEJMoa1210093","article-title":"Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations","volume":"367","author":"Flaherty","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.bbcan.2019.02.002","article-title":"Many ways to resistance: How melanoma cells evade targeted therapies","volume":"1871","author":"Kozar","year":"2019","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"5749","DOI":"10.1158\/1078-0432.CCR-13-0661","article-title":"Identification of multiple mechanisms of resistance to vemurafenib in a patient with BRAFV600E-mutated cutaneous melanoma successfully rechallenged after progression","volume":"19","author":"Romano","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1126\/science.aad0501","article-title":"Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq","volume":"352","author":"Tirosh","year":"2016","journal-title":"Science"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-3-319-22539-5_1","article-title":"Heterogeneity in Melanoma","volume":"167","author":"Shannan","year":"2016","journal-title":"Cancer Treat. Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1158\/1535-7163.MCT-16-0535","article-title":"The Slow Cycling Phenotype: A Growing Problem for Treatment Resistance in Melanoma","volume":"16","author":"Ahn","year":"2017","journal-title":"Mol. Cancer Ther."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"4701","DOI":"10.1182\/blood-2002-09-2780","article-title":"Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment","volume":"101","author":"Bhatia","year":"2003","journal-title":"Blood"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/nrc1590","article-title":"Tumour stem cells and drug resistance","volume":"5","author":"Dean","year":"2005","journal-title":"Nat. Rev. Cancer"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Dylla, S.J., Beviglia, L., Park, I.K., Chartier, C., Raval, J., Ngan, L., Pickell, K., Aguilar, J., Lazetic, S., and Smith-Berdan, S. (2008). Colorectal cancer stem cells are enriched in xenogeneic tumors following chemotherapy. PLoS ONE, 3.","DOI":"10.1371\/annotation\/2aa6a20a-e63c-49b6-aeea-aae62435617f"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"4741","DOI":"10.1038\/onc.2010.215","article-title":"EMT, cancer stem cells and drug resistance: An emerging axis of evil in the war on cancer","volume":"29","author":"Singh","year":"2010","journal-title":"Oncogene"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"78466","DOI":"10.18632\/oncotarget.19638","article-title":"Characterization and functional analysis of a slow-cycling subpopulation in colorectal cancer enriched by cell cycle inducer combined chemotherapy","volume":"8","author":"Wu","year":"2017","journal-title":"Oncotarget"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1038\/nature22993","article-title":"Tracing the origins of relapse in acute myeloid leukaemia to stem cells","volume":"547","author":"Shlush","year":"2017","journal-title":"Nature"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1016\/j.ccr.2013.05.003","article-title":"Overcoming intrinsic multidrug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1B(high) cells","volume":"23","author":"Roesch","year":"2013","journal-title":"Cancer Cell"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/labinvest.2016.140","article-title":"Vemurafenib and trametinib reduce expression of CTGF and IL-8 in V600EBRAF melanoma cells","volume":"97","author":"Hartman","year":"2017","journal-title":"Lab. Investig."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1822","DOI":"10.1089\/scd.2011.0477","article-title":"Slow-cycling therapy-resistant cancer cells","volume":"21","author":"Moore","year":"2012","journal-title":"Stem Cells Dev."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1016\/j.radonc.2013.10.040","article-title":"CD133+ cells contribute to radioresistance via altered regulation of DNA repair genes in human lung cancer cells","volume":"110","author":"Desai","year":"2014","journal-title":"Radiother. Oncol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1863","DOI":"10.1158\/1535-7163.MCT-11-1044","article-title":"A role for homologous recombination and abnormal cell-cycle progression in radioresistance of glioma-initiating cells","volume":"11","author":"Lim","year":"2012","journal-title":"Mol. Cancer Ther."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"4411","DOI":"10.1073\/pnas.1421365112","article-title":"Enhanced expression of DNA polymerase eta contributes to cisplatin resistance of ovarian cancer stem cells","volume":"112","author":"Srivastava","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1158\/1078-0432.CCR-15-1348","article-title":"RAD51 Mediates Resistance of Cancer Stem Cells to PARP Inhibition in Triple-Negative Breast Cancer","volume":"23","author":"Liu","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.molcel.2017.04.006","article-title":"DNA Damage in Stem Cells","volume":"66","author":"Vitale","year":"2017","journal-title":"Mol. Cell"},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Schulz, A., Meyer, F., Dubrovska, A., and Borgmann, K. (2019). Cancer Stem Cells and Radioresistance: DNA Repair and Beyond. Cancers, 11.","DOI":"10.3390\/cancers11060862"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"15030","DOI":"10.1038\/celldisc.2015.30","article-title":"Increased CD271 expression by the NF-kB pathway promotes melanoma cell survival and drives acquired resistance to BRAF inhibitor vemurafenib","volume":"1","author":"Lehraiki","year":"2015","journal-title":"Cell Discov."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"5712","DOI":"10.1038\/ncomms6712","article-title":"Low MITF\/AXL ratio predicts early resistance to multiple targeted drugs in melanoma","volume":"5","author":"Krijgsman","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/nature09161","article-title":"Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271","volume":"466","author":"Boiko","year":"2010","journal-title":"Nature"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"3098","DOI":"10.1158\/0008-5472.CAN-10-3997","article-title":"Human CD271-positive melanoma stem cells associated with metastasis establish tumor heterogeneity and long-term growth","volume":"71","author":"Civenni","year":"2011","journal-title":"Cancer Res."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Redmer, T., Welte, Y., Behrens, D., Fichtner, I., Przybilla, D., Wruck, W., Yaspo, M.L., Lehrach, H., Sch\u00e4fer, R., and Regenbrecht, C.R. (2014). The nerve growth factor receptor CD271 is crucial to maintain tumorigenicity and stem-like properties of melanoma cells. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0092596"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"e291","DOI":"10.1038\/oncsis.2016.88","article-title":"The role of the cancer stem cell marker CD271 in DNA damage response and drug resistance of melanoma cells","volume":"6","author":"Redmer","year":"2017","journal-title":"Oncogenesis"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"7696","DOI":"10.1038\/s41598-019-42773-y","article-title":"CD271 is a molecular switch with divergent roles in melanoma and melanocyte development","volume":"9","author":"Filipp","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1080\/15384101.2016.1152430","article-title":"Targeting NEK2 as a promising therapeutic approach for cancer treatment","volume":"15","author":"Fang","year":"2016","journal-title":"Cell Cycle"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"e101863","DOI":"10.15252\/embj.2019101863","article-title":"Histone H2A phosphorylation recruits topoisomerase II\u03b1 to centromeres to safeguard genomic stability","volume":"39","author":"Zhang","year":"2020","journal-title":"EMBO J."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.dnarep.2017.09.008","article-title":"Role of RAD51AP1 in homologous recombination DNA repair and carcinogenesis","volume":"59","author":"Pires","year":"2017","journal-title":"DNA Repair"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2849","DOI":"10.1038\/s41467-019-10408-5","article-title":"DNA requirement in FANCD2 deubiquitination by USP1-UAF1-RAD51AP1 in the Fanconi anemia DNA damage response","volume":"10","author":"Liang","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/j.cell.2010.04.020","article-title":"A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth","volume":"141","author":"Roesch","year":"2010","journal-title":"Cell"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"7096","DOI":"10.1073\/pnas.1324036111","article-title":"Histone demethylase KDM5B is a key regulator of genome stability","volume":"111","author":"Li","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1016\/j.celrep.2018.09.081","article-title":"Jumonji inhibitors overcome radioresistance in cancer through changes in H3K4 methylation at double-strand breaks","volume":"25","author":"Bayo","year":"2018","journal-title":"Cell. Rep."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.ejca.2018.12.024","article-title":"Sequence-dependent cross-resistance of combined radiotherapy plus BRAFV600E inhibition in melanoma","volume":"109","author":"Shannan","year":"2019","journal-title":"Eur. J. Cancer"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1186\/s12943-019-1090-3","article-title":"AXL receptor tyrosine kinase as a promising anti-cancer approach: Functions, molecular mechanisms and clinical applications","volume":"18","author":"Zhu","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"2601","DOI":"10.1158\/1078-0432.CCR-14-2648","article-title":"AXL Is a Logical Molecular Target in Head and Neck Squamous Cell Carcinoma","volume":"21","author":"Brand","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1158\/1541-7786.MCR-16-0157","article-title":"AXL Inhibition Suppresses the DNA Damage Response and Sensitizes Cells to PARP Inhibition in Multiple Cancers","volume":"15","author":"Balaji","year":"2017","journal-title":"Mol. Cancer Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1172\/JCI85610","article-title":"Inhibition of the GAS6\/AXL pathway augments the efficacy of chemotherapies","volume":"127","author":"Kariolis","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.7150\/thno.15083","article-title":"Gas6\/Axl Axis Contributes to Chemoresistance and Metastasis in Breast Cancer through Akt\/GSK-3\u03b2\/\u03b2-catenin Signaling","volume":"6","author":"Wang","year":"2016","journal-title":"Theranostics"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"3275","DOI":"10.1038\/s41388-018-0205-4","article-title":"AXL\/AKT axis mediated-resistance to BRAF inhibitor depends on PTEN status in melanoma","volume":"37","author":"Zuo","year":"2018","journal-title":"Oncogene"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"6239","DOI":"10.1158\/1078-0432.CCR-17-1284","article-title":"Targeting AXL and mTOR Pathway Overcomes Primary and Acquired Resistance to WEE1 Inhibition in Small-Cell Lung Cancer","volume":"23","author":"Sen","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1158\/1535-7163.MCT-19-0290","article-title":"Targeting AXL and the DNA Damage Response Pathway as a Novel Therapeutic Strategy in Melanoma","volume":"19","author":"McFadden","year":"2020","journal-title":"Mol. Cancer Ther."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/B978-0-12-380888-2.00003-0","article-title":"The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer","volume":"108","author":"Smith","year":"2010","journal-title":"Adv. Cancer Res."},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Hartman, M.L., Sztiller-Sikorska, M., Gajos-Michniewicz, A., and Czyz, M. (2020). Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity. Cells, 9.","DOI":"10.3390\/cells9010142"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"e2135","DOI":"10.1038\/cddis.2015.369","article-title":"Overcoming MITF-conferred drug resistance through dual AURKA\/MAPK targeting in human melanoma cells","volume":"7","author":"Pathria","year":"2016","journal-title":"Cell Death Dis."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"387","DOI":"10.21037\/atm.2017.06.09","article-title":"Overcoming resistance to BRAF inhibitors","volume":"5","author":"Arozarena","year":"2017","journal-title":"Ann. Transl. Med."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1097\/CMR.0b013e328362f9cd","article-title":"Association of MITF and other melanosome-related proteins with chemoresistance in melanoma tumors and cell lines","volume":"23","author":"Azimi","year":"2013","journal-title":"Melanoma Res."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"3616","DOI":"10.1038\/s41388-018-0661-x","article-title":"Lineage-specific control of TFIIH by MITF determines transcriptional homeostasis and DNA repair","volume":"38","author":"Seoane","year":"2019","journal-title":"Oncogene"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1111\/j.1755-148X.2011.00862.x","article-title":"BRCA1 is a new MITF target gene","volume":"24","author":"Beuret","year":"2011","journal-title":"Pigment Cell Melanoma Res."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"2319","DOI":"10.1038\/onc.2010.612","article-title":"Essential role of microphthalmia transcription factor for DNA replication, mitosis and genomic stability in melanoma","volume":"30","author":"Strub","year":"2011","journal-title":"Oncogene"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"3067","DOI":"10.1158\/0008-5472.CAN-15-2680","article-title":"Enhanced Histone Deacetylase Activity in Malignant Melanoma Provokes RAD51 and FANCD2-Triggered Drug Resistance","volume":"76","author":"Krumm","year":"2016","journal-title":"Cancer Res."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"2844","DOI":"10.1002\/ijc.29332","article-title":"MGMT promoter methylation is associated with temozolomide response and prolonged progression-free survival in disseminated cutaneous melanoma","volume":"136","author":"Tuominen","year":"2015","journal-title":"Int. J. Cancer"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1038\/nrneurol.2009.197","article-title":"MGMT promoter methylation in malignant gliomas: Ready for personalized medicine?","volume":"6","author":"Weller","year":"2010","journal-title":"Nat. Rev. Neurol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"4014","DOI":"10.1038\/sj.onc.1207505","article-title":"Profiling epigenetic inactivation of tumor suppressor genes in tumors and plasma from cutaneous melanoma patients","volume":"23","author":"Hoon","year":"2004","journal-title":"Oncogene"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1038\/sj.bjc.6605796","article-title":"MGMT gene promoter methylation correlates with tolerance of temozolomide treatment in melanoma but not with clinical outcome","volume":"103","author":"Hassel","year":"2010","journal-title":"Br. J. Cancer"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"654","DOI":"10.3892\/or.2012.1826","article-title":"Predictive value of the MGMT promoter methylation status in metastatic melanoma patients receiving first-line temozolomide plus bevacizumab in the trial SAKK 50\/07","volume":"28","author":"Schraml","year":"2012","journal-title":"Oncol. Rep."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"4749","DOI":"10.1158\/1078-0432.CCR-18-3625","article-title":"Inhibiting BRAF Oncogene-Mediated Radioresistance Effectively Radiosensitizes BRAFV600E-Mutant Thyroid Cancer Cells by Constraining DNA Double-Strand Break Repair","volume":"25","author":"Robb","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"3713","DOI":"10.1080\/15384101.2015.1104437","article-title":"MEK inhibitor GSK1120212-mediated radiosensitization of pancreatic cancer cells involves inhibition of DNA double-strand break repair pathways","volume":"14","author":"Chatterjee","year":"2015","journal-title":"Cell Cycle"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.ccell.2014.11.018","article-title":"Tunable-combinatorial mechanisms of acquired resistance limit the efficacy of BRAF\/MEK cotargeting but result in melanoma drug addiction","volume":"27","author":"Moriceau","year":"2015","journal-title":"Cancer Cell"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/nature11814","article-title":"Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance","volume":"494","author":"Salangsang","year":"2013","journal-title":"Nature"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1038\/nature09626","article-title":"Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation","volume":"468","author":"Nazarian","year":"2010","journal-title":"Nature"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1016\/j.cell.2015.07.061","article-title":"Non-genomic and Immune Evolution of Melanoma Acquiring MAPKi Resistance","volume":"162","author":"Hugo","year":"2015","journal-title":"Cell"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"4590","DOI":"10.1093\/nar\/gkx126","article-title":"RAD51 interconnects between DNA replication, DNA repair and immunity","volume":"45","author":"Bhattacharya","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"8736","DOI":"10.1158\/0008-5472.CAN-10-0902","article-title":"Basal and treatment-induced activation of AKT mediates resistance to cell death by AZD6244 (ARRY-142886) in Braf-mutant human cutaneous melanoma cells","volume":"70","author":"Gopal","year":"2010","journal-title":"Cancer Res."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1111\/j.1755-148X.2011.00950.x","article-title":"Role and therapeutic potential of PI3K-mTOR signaling in de novo resistance to BRAF inhibition","volume":"25","author":"Deng","year":"2012","journal-title":"Pigment Cell Melanoma Res."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.cell.2006.11.042","article-title":"Essential role for nuclear PTEN in maintaining chromosomal integrity","volume":"128","author":"Shen","year":"2007","journal-title":"Cell"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"7620","DOI":"10.1038\/ncomms8620","article-title":"PTEN regulates DNA replication progression and stalled fork recovery","volume":"6","author":"He","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"17873","DOI":"10.1038\/srep17873","article-title":"PTEN stabilizes TOP2A and regulates the DNA decatenation","volume":"5","author":"Kang","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1158\/1541-7786.MCR-17-0581","article-title":"PTEN Regulates Nonhomologous End Joining By Epigenetic Induction of NHEJ1\/XLF","volume":"16","author":"Sulkowski","year":"2018","journal-title":"Mol. Cancer Res."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1002\/emmm.200900041","article-title":"Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors","volume":"1","author":"Martin","year":"2009","journal-title":"EMBO Mol. Med."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.18632\/oncotarget.26654","article-title":"Synthetic lethality of a cell-penetrating anti-RAD51 antibody in PTEN-deficient melanoma and glioma cells","volume":"10","author":"Turchick","year":"2019","journal-title":"Oncotarget"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1007\/s00018-011-0878-0","article-title":"Genetic alterations of PTEN in human melanoma","volume":"69","author":"Li","year":"2012","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1016\/S0002-9440(10)64627-5","article-title":"Epigenetic PTEN silencing in malignant melanomas without PTEN mutation","volume":"157","author":"Zhou","year":"2000","journal-title":"Am. J. Pathol."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"6546","DOI":"10.1158\/0008-5472.CAN-06-0384","article-title":"Epigenetic silencing of the PTEN gene in melanoma","volume":"66","author":"Mirmohammadsadegh","year":"2006","journal-title":"Cancer Res."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1038\/s41418-017-0030-2","article-title":"Lysyl oxidase-like 3 is required for melanoma cell survival by maintaining genomic stability","volume":"25","author":"Santos","year":"2018","journal-title":"Cell Death Differ."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"3710","DOI":"10.1038\/s41388-018-0640-2","article-title":"Thymine DNA glycosylase as a novel target for melanoma","volume":"38","author":"Mancuso","year":"2019","journal-title":"Oncogene"},{"key":"ref_144","doi-asserted-by":"crossref","unstructured":"Burkel, F., Jost, T., Hecht, M., Heinzerling, L., Fietkau, R., and Distel, L. (2020). Dual mTOR\/DNA-PK Inhibitor CC-115 Induces Cell Death in Melanoma Cells and Has Radiosensitizing Potential. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21239321"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"86","DOI":"10.3389\/fonc.2018.00086","article-title":"Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations","volume":"8","author":"Seidel","year":"2018","journal-title":"Front. Oncol."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1182\/blood-2017-06-741033","article-title":"CTLA-4: A moving target in immunotherapy","volume":"131","author":"Rowshanravan","year":"2018","journal-title":"Blood"},{"key":"ref_147","first-page":"75","article-title":"Role of PD-1 in Immunity and Diseases","volume":"410","author":"Chamoto","year":"2017","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1056\/NEJMoa1003466","article-title":"Improved survival with ipilimumab in patients with metastatic melanoma","volume":"363","author":"Hodi","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1016\/S0140-6736(17)31601-X","article-title":"Pembrolizumab versus ipilimumab for advanced melanoma: Final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006)","volume":"390","author":"Schachter","year":"2017","journal-title":"Lancet"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1056\/NEJMoa1504030","article-title":"Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma","volume":"373","author":"Larkin","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"2521","DOI":"10.1056\/NEJMoa1503093","article-title":"Pembrolizumab versus Ipilimumab in Advanced Melanoma","volume":"372","author":"Robert","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.cell.2016.02.065","article-title":"Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma","volume":"165","author":"Hugo","year":"2016","journal-title":"Cell"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1056\/NEJMoa1709684","article-title":"Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma","volume":"377","author":"Wolchok","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"2143","DOI":"10.1002\/cncr.30444","article-title":"Immune and molecular correlates in melanoma treated with immune checkpoint blockade","volume":"123","author":"Byrne","year":"2017","journal-title":"Cancer"},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1038\/nrc.2017.117","article-title":"Impact of oncogenic pathways on evasion of antitumour immune responses","volume":"18","author":"Spranger","year":"2018","journal-title":"Nat. Rev. Cancer"},{"key":"ref_156","doi-asserted-by":"crossref","unstructured":"Paijens, S.T., Vledder, A., de Bruyn, M., and Nijman, H.W. (2020). Tumor-infiltrating lymphocytes in the immunotherapy era. Cell. Mol. Immunol.","DOI":"10.1038\/s41423-020-00565-9"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"2105","DOI":"10.3389\/fimmu.2020.02105","article-title":"Tumor-Infiltrating Lymphocytes and Their Prognostic Value in Cutaneous Melanoma","volume":"11","author":"Maibach","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1038\/nature13954","article-title":"PD-1 blockade induces responses by inhibiting adaptive immune resistance","volume":"515","author":"Tumeh","year":"2014","journal-title":"Nature"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1186\/s12935-019-0929-4","article-title":"Tumor mutation burden: From comprehensive mutational screening to the clinic","volume":"19","author":"Galuppini","year":"2019","journal-title":"Cancer Cell Int."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1038\/nature12477","article-title":"Signatures of mutational processes in human cancer","volume":"500","author":"Alexandrov","year":"2013","journal-title":"Nature."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"2189","DOI":"10.1056\/NEJMoa1406498","article-title":"Genetic basis for clinical response to CTLA-4 blockade in melanoma","volume":"371","author":"Snyder","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1158\/2326-6066.CIR-16-0143","article-title":"Targeted Next Generation Sequencing Identifies Markers of Response to PD-1 Blockade","volume":"4","author":"Chalmers","year":"2016","journal-title":"Cancer Immunol. Res."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1126\/science.aad0095","article-title":"Genomic correlates of response to CTLA-4 blockade in metastatic melanoma","volume":"350","author":"Miao","year":"2015","journal-title":"Science"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1056\/NEJMoa1604958","article-title":"Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma","volume":"375","author":"Zaretsky","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1038\/s41467-020-15726-7","article-title":"Transcriptional downregulation of MHC class I and melanoma de- differentiation in resistance to PD-1 inhibition","volume":"11","author":"Lee","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"27","DOI":"10.3389\/fmed.2019.00027","article-title":"Immune Cell Infiltration of the Primary Tumor, Not PD-L1 Status, Is Associated With Improved Response to Checkpoint Inhibition in Metastatic Melanoma","volume":"6","author":"Jokic","year":"2019","journal-title":"Front. Med."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"4252","DOI":"10.1200\/JCO.2013.51.3002","article-title":"Tumor-infiltrating lymphocyte grade in primary melanomas is independently associated with melanoma-specific survival in the population-based genes, environment and melanoma study","volume":"31","author":"Thomas","year":"2013","journal-title":"J. Clin. Oncol."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"187","DOI":"10.2217\/mmt-2016-0013","article-title":"PD-L1 in melanoma: Facts and myths","volume":"3","author":"Merelli","year":"2016","journal-title":"Melanoma Manag."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"185","DOI":"10.3389\/fphar.2018.00185","article-title":"Combining Immunotherapy and Radiotherapy for Cancer Treatment: Current Challenges and Future Directions","volume":"9","author":"Wang","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.3389\/fonc.2019.01009","article-title":"Altering DNA Repair to Improve Radiation Therapy: Specific and Multiple Pathway Targeting","volume":"9","author":"Biau","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1001\/jamaoncol.2015.2756","article-title":"Role of Local Radiation Therapy in Cancer Immunotherapy","volume":"1","author":"Demaria","year":"2015","journal-title":"JAMA Oncol."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1084\/jem.20052494","article-title":"Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy","volume":"203","author":"Reits","year":"2006","journal-title":"J. Exp. Med."},{"key":"ref_173","first-page":"390","article-title":"Radiation-induced tumor neoantigens: Imaging and therapeutic implications","volume":"1","author":"Corso","year":"2011","journal-title":"Am. J. Cancer Res."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"e498","DOI":"10.1016\/S1470-2045(15)00007-8","article-title":"Radiation and checkpoint blockade immunotherapy: Radiosensitisation and potential mechanisms of synergy","volume":"16","author":"Sharabi","year":"2015","journal-title":"Lancet Oncol."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"192","DOI":"10.3389\/fonc.2018.00192","article-title":"Radiation-Induced Chromosomal Aberrations and Immunotherapy: Micronuclei, Cytosolic DNA, and Interferon-Production Pathway","volume":"8","author":"Durante","year":"2018","journal-title":"Front. Oncol."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1016\/j.immuni.2014.10.017","article-title":"STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors","volume":"41","author":"Woo","year":"2014","journal-title":"Immunity"},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1016\/j.immuni.2018.07.008","article-title":"Non-canonical NF-\u03baB Antagonizes STING Sensor-Mediated DNA Sensing in Radiotherapy","volume":"49","author":"Hou","year":"2018","journal-title":"Immunity"},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1038\/s41580-020-0244-x","article-title":"Molecular mechanisms and cellular functions of cGAS-STING signalling","volume":"21","author":"Hopfner","year":"2020","journal-title":"Nat. Rev. Mol. Cell. Biol."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1016\/j.immuni.2014.10.019","article-title":"STING-Dependent Cytosolic DNA Sensing Promotes Radiation-Induced Type I Interferon-Dependent Antitumor Immunity in Immunogenic Tumors","volume":"41","author":"Deng","year":"2014","journal-title":"Immunity"},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2478\/v10019-010-0008-x","article-title":"Role of radiotherapy in melanoma management","volume":"44","author":"Strojan","year":"2010","journal-title":"Radiol. Oncol."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.ygyno.2019.03.097","article-title":"Mismatch repair deficiency as a predictive marker for response to adjuvant radiotherapy in endometrial cancer","volume":"154","author":"Reijnen","year":"2019","journal-title":"Gynecol. Oncol."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"5458","DOI":"10.1158\/0008-5472.CAN-14-1258","article-title":"Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade","volume":"74","author":"Dovedi","year":"2014","journal-title":"Cancer Res."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"610","DOI":"10.3389\/fimmu.2016.00610","article-title":"Chemoradiation Increases PD-L1 Expression in Certain Melanoma and Glioblastoma Cells","volume":"7","author":"Derer","year":"2016","journal-title":"Front. Immunol."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1038\/nature14292","article-title":"Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer","volume":"520","author":"Rech","year":"2015","journal-title":"Nature"},{"key":"ref_185","first-page":"e3860","article-title":"Abscopal Effect, From Myth to Reality: From Radiation Oncologists\u2019 Perspective","volume":"11","author":"Yilmaz","year":"2019","journal-title":"Cureus"},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1038\/nature23470","article-title":"Mitotic progression following DNA damage enables pattern recognition within micronuclei","volume":"548","author":"Harding","year":"2017","journal-title":"Nature"},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.ijrobp.2012.03.017","article-title":"The abscopal effect associated with a systemic anti-melanoma immune response","volume":"85","author":"Stamell","year":"2013","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1056\/NEJMoa1112824","article-title":"Immunologic correlates of the abscopal effect in a patient with melanoma","volume":"366","author":"Postow","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1158\/2326-6066.CIR-14-0138","article-title":"PD-1 Restrains Radiotherapy-Induced Abscopal Effect","volume":"3","author":"Park","year":"2015","journal-title":"Cancer Immunol. Res."},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1097\/CJI.0000000000000141","article-title":"Analysis of the Abscopal Effect With Anti-PD1 Therapy in Patients With Metastatic Solid Tumors","volume":"39","author":"Schmerling","year":"2016","journal-title":"J. Immunother."},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"511","DOI":"10.3389\/fphar.2019.00511","article-title":"Abscopal Effects in Radio-Immunotherapy-Response Analysis of Metastatic Cancer Patients With Progressive Disease Under Anti-PD-1 Immune Checkpoint","volume":"10","author":"Trommer","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.wneu.2019.04.093","article-title":"Optimal Timing and Sequence of Immunotherapy When Combined with Stereotactic Radiosurgery in the Treatment of Brain Metastases","volume":"127","author":"ElJalby","year":"2019","journal-title":"World Neurosurg."},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"3051","DOI":"10.1002\/cncr.30138","article-title":"Timing and type of immune checkpoint therapy affect the early radiographic response of melanoma brain metastases to stereotactic radiosurgery","volume":"122","author":"Qian","year":"2016","journal-title":"Cancer"},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1097\/COC.0000000000000199","article-title":"Ipilimumab and Stereotactic Radiosurgery Versus Stereotactic Radiosurgery Alone for Newly Diagnosed Melanoma Brain Metastases","volume":"40","author":"Patel","year":"2017","journal-title":"Am. J. Clin. Oncol."},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"e000395","DOI":"10.1136\/jitc-2019-000395","article-title":"Impact of a preceding radiotherapy on the outcome of immune checkpoint inhibition in metastatic melanoma: A multicenter retrospective cohort study of the DeCOG","volume":"8","author":"Knispel","year":"2020","journal-title":"J. Immunother. Cancer"},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1158\/2159-8290.CD-17-0226","article-title":"DNA Damage and Repair Biomarkers of Immunotherapy Response","volume":"7","author":"Mouw","year":"2017","journal-title":"Cancer Discov."},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s40364-020-00202-7","article-title":"Role of DNA repair defects in predicting immunotherapy response","volume":"8","author":"Zhang","year":"2020","journal-title":"Biomark. Res."},{"key":"ref_198","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.1056\/NEJMoa1500596","article-title":"PD-1 Blockade in Tumors with Mismatch-Repair Deficiency","volume":"372","author":"Le","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.ccell.2015.06.012","article-title":"Mismatch Repair-Deficient Cancers Are Targets for Anti-PD-1 Therapy","volume":"28","author":"Kelderman","year":"2015","journal-title":"Cancer Cell"},{"key":"ref_200","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1056\/NEJMp1709968","article-title":"First FDA Approval Agnostic of Cancer Site\u2014When a Biomarker Defines the Indication","volume":"377","author":"Lemery","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_201","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1038\/s41588-020-00739-1","article-title":"Integrated molecular drivers coordinate biological and clinical states in melanoma","volume":"52","author":"Conway","year":"2020","journal-title":"Nat. Genet."},{"key":"ref_202","first-page":"3","article-title":"Immunohistochemical mismatch repair proteins expression as a tool to predict the melanoma immunotherapy response","volume":"12","author":"Ponti","year":"2020","journal-title":"Mol. Clin. Oncol."},{"key":"ref_203","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1126\/science.aau0447","article-title":"Genetic diversity of tumors with mismatch repair deficiency influences anti-PD-1 immunotherapy response","volume":"364","author":"Mandal","year":"2019","journal-title":"Science"},{"key":"ref_204","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1016\/j.neo.2014.08.008","article-title":"A preclinical study combining the DNA repair inhibitor Dbait with radiotherapy for the treatment of melanoma","volume":"16","author":"Biau","year":"2014","journal-title":"Neoplasia"},{"key":"ref_205","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1038\/bjc.2016.120","article-title":"First-in-human phase I study of the DNA-repair inhibitor DT01 in combination with radiotherapy in patients with skin metastases from melanoma","volume":"114","author":"Dreno","year":"2016","journal-title":"Br. J. Cancer"},{"key":"ref_206","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1158\/2326-6066.CIR-15-0044","article-title":"CTLA-4 Blockade Synergizes Therapeutically with PARP Inhibition in BRCA1-Deficient Ovarian Cancer","volume":"3","author":"Higuchi","year":"2015","journal-title":"Cancer Immunol. Res."},{"key":"ref_207","doi-asserted-by":"crossref","first-page":"3711","DOI":"10.1158\/1078-0432.CCR-16-3215","article-title":"PARP Inhibitor Upregulates PD-L1 Expression and Enhances Cancer-Associated Immunosuppression","volume":"23","author":"Jiao","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_208","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1158\/1078-0432.CCR-16-1193","article-title":"Drug-Driven Synthetic Lethality: Bypassing Tumor Cell Genetics with a Combination of AsiDNA and PARP Inhibitors","volume":"23","author":"Jdey","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_209","unstructured":"(2021, March 23). Clinical Trials, Available online: https:\/\/clinicaltrials.gov\/ct2\/home."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/7\/3485\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:10:14Z","timestamp":1760364614000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/7\/3485"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,28]]},"references-count":209,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["ijms22073485"],"URL":"https:\/\/doi.org\/10.3390\/ijms22073485","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,28]]}}}