{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T01:56:24Z","timestamp":1791597384811,"version":"4.3.4"},"reference-count":179,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T00:00:00Z","timestamp":1755734400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"\u201cCurrent Research\u201d funds from the Italian Ministry of Health"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Melanoma, the deadliest human skin cancer, frequently harbors activating BRAF mutations, with V600E being the most prevalent. These alterations drive constitutive activation of the MAPK pathway, promoting uncontrolled cell proliferation, survival, and dissemination. The advent of BRAFi and MEKi has significantly improved outcomes in BRAF V600-mutant melanoma. However, therapeutic resistance remains a major clinical barrier. Methods: This review integrates recent findings from preclinical and clinical studies to delineate resistance mechanisms to BRAF-targeted therapy. It categorizes resistance into primary (intrinsic), adaptive, and acquired forms, and analyzes their molecular underpinnings, including genetic and epigenetic alterations, pathway reactivation, and microenvironmental interactions. Results: Primary resistance is linked to pre-existing genetic and epigenetic changes that activate alternative signaling pathways, such as PI3K-AKT. Adaptive and acquired resistance includes secondary BRAF mutations, pathway redundancy, phenotype switching, and immune and stromal interactions. High-throughput sequencing has revealed novel mutations, including NRAS, NF1, and PTEN alterations, that contribute to resistance. Discussion: Understanding the multifaceted nature of resistance is critical to improving outcomes in advanced melanoma. This review highlights emerging strategies to overcome resistance, including combinatorial therapies, metabolic targeting, and biomarker-driven approaches, aiming to inform future therapeutic development and precision oncology strategies.<\/jats:p>","DOI":"10.3390\/ph18081235","type":"journal-article","created":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T14:46:04Z","timestamp":1755787564000},"page":"1235","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Molecular Basis of BRAF Inhibitor Resistance in Melanoma: A Systematic Review"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-5998-8146","authenticated-orcid":false,"given":"Ilaria","family":"Cosci","sequence":"first","affiliation":[{"name":"Unit of Andrology and Reproductive Medicine, Department of Medicine, University of Padova, 35122 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1027-3259","authenticated-orcid":false,"given":"Valentina","family":"Salizzato","sequence":"additional","affiliation":[{"name":"Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2862-8014","authenticated-orcid":false,"given":"Paolo","family":"Del Fiore","sequence":"additional","affiliation":[{"name":"Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2427-8915","authenticated-orcid":false,"given":"Jacopo","family":"Pigozzo","sequence":"additional","affiliation":[{"name":"Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Guarneri","sequence":"additional","affiliation":[{"name":"Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy"},{"name":"Department of Surgical, Oncological and Gastroenterological Sciences (DISCOG), University of Padova, 35138 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9433-8445","authenticated-orcid":false,"given":"Simone","family":"Mocellin","sequence":"additional","affiliation":[{"name":"Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy"},{"name":"Department of Surgical, Oncological and Gastroenterological Sciences (DISCOG), University of Padova, 35138 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5817-8141","authenticated-orcid":false,"given":"Alberto","family":"Ferlin","sequence":"additional","affiliation":[{"name":"Unit of Andrology and Reproductive Medicine, Department of Medicine, University of Padova, 35122 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3962-615X","authenticated-orcid":false,"given":"Sara","family":"Mathlouthi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"Piccin","sequence":"additional","affiliation":[{"name":"Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5001-7826","authenticated-orcid":false,"given":"Mariangela","family":"Garofalo","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,21]]},"reference":[{"key":"ref_1","unstructured":"American Cancer Society (2021). Cancer Facts and Figures 2021, American Cancer Society."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1007\/s40257-023-00795-3","article-title":"Global Incidence, Mortality, Risk Factors and Trends of Melanoma: A Systematic Analysis of Registries","volume":"24","author":"Huang","year":"2023","journal-title":"Am. J. Clin. Dermatol."},{"key":"ref_3","unstructured":"American Cancer Society (2022). Survival Rates for Melanoma Skin Cancer 2022, American Cancer Society."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.1158\/1078-0432.CCR-1169-3","article-title":"Incidence of BRAF Oncogene Mutation and Clinical Relevance for Primary Cutaneous Melanomas","volume":"10","author":"Shinozaki","year":"2004","journal-title":"Clin. Cancer Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"78174","DOI":"10.18632\/oncotarget.19836","article-title":"BRAF Inhibitors: Resistance and the Promise of Combination Treatments for Melanoma","volume":"8","author":"Griffin","year":"2017","journal-title":"Oncotarget"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1016\/j.bbamcr.2006.10.001","article-title":"Roles of the Raf\/MEK\/ERK Pathway in Cell Growth, Malignant Transformation and Drug Resistance","volume":"1773","author":"McCubrey","year":"2007","journal-title":"Biochim. Biophys. Acta Mol. Cell. Res."},{"key":"ref_7","first-page":"3728","article-title":"Mitogen-Actived Protein Kinase Activation Is an Early Event in Melanoma Progression","volume":"8","author":"Cohen","year":"2002","journal-title":"Clin. Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1038\/nature00766","article-title":"Mutations of the BRAF Gene in Human Cancer","volume":"417","author":"Davies","year":"2002","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Florent, L., Saby, C., Slimano, F., and Morjani, H. (2023). BRAF V600-Mutated Metastatic Melanoma and Targeted Therapy Resistance: An Update of the Current Knowledge. Cancers, 15.","DOI":"10.3390\/cancers15092607"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Ottaviano, M., Giunta, E.F., Tortora, M., Curvietto, M., Attademo, L., Bosso, D., Cardalesi, C., Rosanova, M., De Placido, P., and Pietroluongo, E. (2021). BRAF Gene and Melanoma: Back to the Future. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22073474"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/modpathol.2017.104","article-title":"Molecular Testing for BRAF Mutations to Inform Melanoma Treatment Decisions: A Move toward Precision Medicine","volume":"31","author":"Cheng","year":"2018","journal-title":"Mod. Pathol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2012","DOI":"10.1016\/j.celrep.2016.04.073","article-title":"Oncogenic BRAF-Mediated Melanoma Cell Invasion","volume":"15","author":"Lu","year":"2016","journal-title":"Cell Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.ccr.2011.01.008","article-title":"Mutant BRAF Melanomas-Dependence and Resistance","volume":"19","author":"Poulikakos","year":"2011","journal-title":"Cancer Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1097\/PPO.0b013e31823e5357","article-title":"BRAF Inhibitors and Melanoma","volume":"17","author":"Flaherty","year":"2011","journal-title":"Cancer J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5339","DOI":"10.1158\/1078-0432.CCR-16-2923","article-title":"Phase I Dose-Escalation and -Expansion Study of the BRAF Inhibitor Encorafenib (LGX818) in Metastatic BRAF-Mutant Melanoma","volume":"23","author":"Delord","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1200\/JCO.2007.12.7837","article-title":"Meta-Analysis of Phase II Cooperative Group Trials in Metastatic Stage IV Melanoma to Determine Progression-Free and Overall Survival Benchmarks for Future Phase II Trials","volume":"26","author":"Korn","year":"2008","journal-title":"J. Clin. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1158\/2159-8290.CD-13-0642","article-title":"Acquired Resistance and Clonal Evolution in Melanoma during BRAF Inhibitor Therapy","volume":"4","author":"Shi","year":"2014","journal-title":"Cancer Discov."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1056\/NEJMoa1904059","article-title":"Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma","volume":"381","author":"Robert","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1016\/S1470-2045(15)00087-X","article-title":"Comparison of Dabrafenib and Trametinib Combination Therapy with Vemurafenib Monotherapy on Health-Related Quality of Life in Patients with Unresectable or Metastatic Cutaneous BRAF Val600-Mutation-Positive Melanoma (COMBI-v): Results of a Phase 3, Open-Label, Randomised Trial","volume":"16","author":"Grob","year":"2015","journal-title":"Lancet Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5225","DOI":"10.1158\/1078-0432.CCR-21-0809","article-title":"5-Year Outcomes with Cobimetinib plus Vemurafenib in BRAFV600 Mutation\u21d3positive Advanced Melanoma: Extended Follow-up of the CoBRIM Study","volume":"27","author":"Ascierto","year":"2021","journal-title":"Clin. Cancer Res."},{"key":"ref_21","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":"The Lancet"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Hamid, O., Cowey, C.L., Offner, M., Faries, M., and Carvajal, R.D. (2019). Efficacy, Safety, and Tolerability of Approved Combination BRAF and MEK Inhibitor Regimens for BRAF-Mutant Melanoma. Cancers, 11.","DOI":"10.3390\/cancers11111642"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.ejca.2019.11.016","article-title":"Update on Tolerability and Overall Survival in COLUMBUS: Landmark Analysis of a Randomised Phase 3 Trial of Encorafenib plus Binimetinib vs Vemurafenib or Encorafenib in Patients with BRAF V600\u2013Mutant Melanoma","volume":"126","author":"Ascierto","year":"2020","journal-title":"Eur. J. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Patel, H., Yacoub, N., Mishra, R., White, A., Yuan, L., Alanazi, S., and Garrett, J.T. (2020). Current Advances in the Treatment of Braf-Mutant Melanoma. Cancers, 12.","DOI":"10.3390\/cancers12020482"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.ejca.2016.12.012","article-title":"MAPK Pathway in Melanoma Part II-Secondary and Adaptive Resistance Mechanisms to BRAF Inhibition","volume":"73","author":"Amaral","year":"2017","journal-title":"Eur. J. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5694","DOI":"10.1038\/ncomms6694","article-title":"Increased MAPK Reactivation in Early Resistance to Dabrafenib\/Trametinib Combination Therapy of BRAF-Mutant Metastatic Melanoma","volume":"5","author":"Long","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1158\/2159-8290.CD-13-0617","article-title":"The Genetic Landscape of Clinical Resistance to RAF Inhibition in Metastatic Melanoma","volume":"4","author":"Wagle","year":"2014","journal-title":"Cancer Discov."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1038\/ng0497-356","article-title":"Identification of a Candidate Tumour Suppressor Gene, MMAC1, at Chromosome 10q23.3 That Is Mutated in Multiple Advanced Cancers","volume":"15","author":"Steck","year":"1997","journal-title":"Nat. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Yu, C., Zhang, M., Song, J., Zheng, X., Xu, G., Bao, Y., Lan, J., Luo, D., Hu, J., and Li, J.J. (2020). Integrin-Src-YAP1 Signaling Mediates the Melanoma Acquired Resistance to MAPK and PI3K\/MTOR Dual Targeted Therapy. Mol. Biomed., 1.","DOI":"10.1186\/s43556-020-00013-0"},{"key":"ref_30","first-page":"2881","article-title":"Loss of PTEN Promotes Tumor Development in Malignant Melanoma","volume":"63","author":"Stahl","year":"2003","journal-title":"Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2750","DOI":"10.1158\/0008-5472.CAN-10-2954","article-title":"PTEN Loss Confers BRAF Inhibitor Resistance to Melanoma Cells through the Suppression of BIM Expression","volume":"71","author":"Paraiso","year":"2011","journal-title":"Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Liu, J., Lin, J., Wang, X., Zheng, X., Gao, X., Huang, Y., Chen, G., Xiong, J., Lan, B., and Chen, C. (2022). CCND1 Amplification Profiling Identifies a Subtype of Melanoma Associated With Poor Survival and an Immunosuppressive Tumor Microenvironment. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.725679"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Czarnecka, A.M., Bartnik, E., Fiedorowicz, M., and Rutkowski, P. (2020). Targeted Therapy in Melanoma and Mechanisms of Resistance. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21134576"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1038\/ng.3361","article-title":"Exome Sequencing Identifies Recurrent Mutations in NF1 and RASopathy Genes in Sun-Exposed Melanomas","volume":"47","author":"Krauthammer","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"dmm049229","DOI":"10.1242\/dmm.049229","article-title":"RAS Pathway Regulation in Melanoma","volume":"15","author":"Ablain","year":"2022","journal-title":"DMM Dis. Models Mech."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1016\/j.trecan.2020.02.021","article-title":"RAC1 as a Therapeutic Target in Malignant Melanoma","volume":"6","author":"Cannon","year":"2020","journal-title":"Trends Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Vachtenheim, J., and Ondru\u0161ov\u00e1, L. (2021). Many Distinct Ways Lead to Drug Resistance in BRAF- and NRAS-Mutated Melanomas. Life, 11.","DOI":"10.3390\/life11050424"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejca.2023.01.009","article-title":"Characterisation and Outcome of RAC1 Mutated Melanoma","volume":"183","author":"Lodde","year":"2023","journal-title":"Eur. J. Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.1084\/jem.20171960","article-title":"Loss of USP28-Mediated BRAF Degradation Drives Resistance to RAF Cancer Therapies","volume":"215","author":"Saei","year":"2018","journal-title":"J. Exp. Med."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Khaliq, M., and Fallahi-Sichani, M. (2019). Epigenetic Mechanisms of Escape from BRAF Oncogene Dependency. Cancers, 11.","DOI":"10.3390\/cancers11101480"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1038\/nature24297","article-title":"Drug-Tolerant Persister Cancer Cells Are Vulnerable to GPX4 Inhibition","volume":"551","author":"Hangauer","year":"2017","journal-title":"Nature"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.tree.2005.06.001","article-title":"Evolution of Phenotypic Plasticity: Where Are We Going Now?","volume":"20","author":"Pigliucci","year":"2005","journal-title":"Trends Ecol. Evol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3426","DOI":"10.1101\/gad.406406","article-title":"Mitf Regulation of Dia1 Controls Melanoma Proliferation and Invasiveness","volume":"20","author":"Carreira","year":"2006","journal-title":"Genes. Dev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1038\/nature05660","article-title":"Melanocyte Biology and Skin Pigmentation","volume":"445","author":"Lin","year":"2007","journal-title":"Nature"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.15252\/emmm.201607156","article-title":"Targeting Endothelin Receptor Signalling Overcomes Heterogeneity Driven Therapy Failure","volume":"9","author":"Smith","year":"2017","journal-title":"EMBO Mol. Med."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Fallahi-Sichani, M., Becker, V., Izar, B., Baker, G.J., Lin, J., Boswell, S.A., Shah, P., Rotem, A., Garraway, L.A., and Sorger, P.K. (2017). Adaptive Resistance of Melanoma Cells to RAF Inhibition via Reversible Induction of a Slowly Dividing De-differentiated State. Mol. Syst. Biol., 13.","DOI":"10.15252\/msb.20166796"},{"key":"ref_47","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_48","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1038\/s41571-019-0204-6","article-title":"Cell-State Dynamics and Therapeutic Resistance in Melanoma from the Perspective of MITF and IFN\u03b3 Pathways","volume":"16","author":"Bai","year":"2019","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1038\/nm.4040","article-title":"Tumor Cells Can Follow Distinct Evolutionary Paths to Become Resistant to Epidermal Growth Factor Receptor Inhibition","volume":"22","author":"Hata","year":"2016","journal-title":"Nat. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1038\/nature22794","article-title":"Rare Cell Variability and Drug-Induced Reprogramming as a Mode of Cancer Drug Resistance","volume":"546","author":"Shaffer","year":"2017","journal-title":"Nature"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1126\/science.1210944","article-title":"Tet-Mediated Formation of 5-Carboxylcytosine and Its Excision by TDG in Mammalian DNA","volume":"333","author":"He","year":"2011","journal-title":"Science"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1126\/science.1210597","article-title":"Tet Proteins Can Convert 5-Methylcytosine to 5-Formylcytosine and 5-Carboxylcytosine","volume":"333","author":"Ito","year":"2011","journal-title":"Science"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/s13148-017-0332-8","article-title":"Aberrant DNA Methylation in Melanoma: Biomarker and Therapeutic Opportunities","volume":"9","author":"Micevic","year":"2017","journal-title":"Clin. Epigenetics"},{"key":"ref_54","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_55","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1097\/CMR.0000000000000315","article-title":"Attenuation of Genome-Wide 5-Methylcytosine Level Is an Epigenetic Feature of Cutaneous Malignant Melanomas","volume":"27","author":"Micevic","year":"2017","journal-title":"Melanoma Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/S0092-8674(00)81079-X","article-title":"Role of the INK4a Locus in Tumor Suppression and Cell Mortality","volume":"85","author":"Serrano","year":"1996","journal-title":"Cell"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2809","DOI":"10.1038\/jid.2010.216","article-title":"High Frequency of P16 INK4A Promoter Methylation in NRAS-Mutated Cutaneous Melanoma","volume":"130","author":"Jonsson","year":"2010","journal-title":"J. Investig. Dermatol."},{"key":"ref_58","first-page":"11","article-title":"Frequent Intra-Tumoural Heterogeneity of Promoter Hypermethylation in Malignant Melanoma","volume":"22","author":"Rastetter","year":"2007","journal-title":"Histol. Histopathol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1016\/S0092-8674(00)81400-2","article-title":"The Ink4a Tumor Suppressor Gene Product, P19Arf, Interacts with MDM2 and Neutralizes MDM2\u2019s Inhibition of P53","volume":"92","author":"Pomerantz","year":"1998","journal-title":"Cell"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1093\/jnci\/djn157","article-title":"Frequent P16-Independent Inactivation of P14ARF in Human Melanoma","volume":"100","author":"Freedberg","year":"2008","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2360","DOI":"10.1002\/jcp.22568","article-title":"RASSF1A Suppresses Melanoma Development by Modulating Apoptosis and Cell-Cycle Progression","volume":"226","author":"Yi","year":"2011","journal-title":"J. Cell Physiol."},{"key":"ref_62","first-page":"394","article-title":"Aberrant DNA Methylation Is Associated with Aggressive Clinicopathological Features and Poor Survival in Cutaneous Melanoma","volume":"179","year":"2018","journal-title":"Br. J. Dermatol."},{"key":"ref_63","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_64","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1038\/301089a0","article-title":"Hypomethylation Distinguishes Genes of Some Human Cancers from Their Normal Counterparts","volume":"301","author":"Feinberg","year":"1983","journal-title":"Nature"},{"key":"ref_65","first-page":"2943","article-title":"Transposable Hypomethylation Is Associated with Metastatic Capacity of Primary Melanomas","volume":"6","author":"Ecsedi","year":"2013","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1038\/nm.3863","article-title":"Epigenetic Activation of a Cryptic TBC1D16 Transcript Enhances Melanoma Progression by Targeting EGFR","volume":"21","author":"Vizoso","year":"2015","journal-title":"Nat. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1016\/j.ccell.2018.01.002","article-title":"Targeting the Senescence-Overriding Cooperative Activity of Structurally Unrelated H3K9 Demethylases in Melanoma","volume":"33","author":"Yu","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.ccell.2018.01.013","article-title":"An Epigenetic Switch: From Senescent Melanocytes to Malignant Melanoma (and Back)","volume":"33","author":"Wagner","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_69","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_70","doi-asserted-by":"crossref","first-page":"4545","DOI":"10.1038\/onc.2014.432","article-title":"A Stress-Induced Early Innate Response Causes Multidrug Tolerance in Melanoma","volume":"34","author":"Menon","year":"2015","journal-title":"Oncogene"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"3440","DOI":"10.1038\/s41467-018-05966-z","article-title":"SIRT6 Haploinsufficiency Induces BRAFV600E Melanoma Cell Resistance to MAPK Inhibitors via IGF Signalling","volume":"9","author":"Strub","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1038\/35021093","article-title":"Molecular Portraits of Human Breast Tumours","volume":"406","author":"Perou","year":"2000","journal-title":"Nature"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/1475-2867-14-18","article-title":"The Basal Transcription Machinery as a Target for Cancer Therapy","volume":"14","author":"Cruz","year":"2014","journal-title":"Cancer Cell Int."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1038\/nature03664","article-title":"Integrative Genomic Analyses Identify MITF as a Lineage Survival Oncogene Amplified in Malignant Melanoma","volume":"436","author":"Garraway","year":"2005","journal-title":"Nature"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"7093","DOI":"10.1038\/s41388-020-01490-x","article-title":"Transcriptional Regulators and Alterations That Drive Melanoma Initiation and Progression","volume":"39","author":"Gupta","year":"2020","journal-title":"Oncogene"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/j.molmed.2006.07.008","article-title":"MITF: Master Regulator of Melanocyte Development and Melanoma Oncogene","volume":"12","author":"Levy","year":"2006","journal-title":"Trends Mol Med"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/nature10630","article-title":"A Novel Recurrent Mutation in MITF Predisposes to Familial and Sporadic Melanoma","volume":"480","author":"Yokoyama","year":"2011","journal-title":"Nature"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1111\/j.1600-0749.2005.00234.x","article-title":"Sumoylation Modulates Transcriptional Activity of MITF in a Promoter-Specific Manner","volume":"18","author":"Murakami","year":"2005","journal-title":"Pigment. Cell Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"11077","DOI":"10.1074\/jbc.M111696200","article-title":"Microphthalmia Transcription Factor Is a Target of the P38 MAPK Pathway in Response to Receptor Activator of NF-\u039aB Ligand Signaling","volume":"277","author":"Mansky","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/s004390050793","article-title":"The SOX10\/Sox10 Gene from Human and Mouse: Sequence, Expression, and Transactivation by the Encoded HMG Domain Transcription Factor","volume":"103","author":"Pusch","year":"1998","journal-title":"Hum. Genet."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1038\/s41467-017-02354-x","article-title":"ERK-Mediated Phosphorylation Regulates SOX10 Sumoylation and Targets Expression in Mutant BRAF Melanoma","volume":"9","author":"Han","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1101\/gad.190678.112","article-title":"Mutant P53: One Name, Many Proteins","volume":"26","author":"Prives","year":"2012","journal-title":"Genes. Dev."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1016\/j.molcel.2011.08.044","article-title":"PGC-1\u03b1, a Key Modulator of P53, Promotes Cell Survival upon Metabolic Stress","volume":"44","author":"Sen","year":"2011","journal-title":"Mol. Cell"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1016\/j.molmed.2010.09.002","article-title":"P53 Post-Translational Modification: Deregulated in Tumorigenesis","volume":"16","author":"Dai","year":"2010","journal-title":"Trends. Mol. Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1186\/s12957-023-03036-3","article-title":"Identification of BRAF, CCND1, and MYC Mutations in a Patient with Multiple Primary Malignant Tumors: A Case Report and Review of the Literature","volume":"21","author":"Liu","year":"2023","journal-title":"World J. Surg. Oncol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"208","DOI":"10.4161\/cc.26971","article-title":"Activities of Multiple Cancer-Related Pathways Are Associated with BRAF Mutation and Predict the Resistance to BRAF\/MEK Inhibitors in Melanoma Cells","volume":"13","author":"Liu","year":"2014","journal-title":"Cell Cycle"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Mukherjee, N., Amato, C.M., Skees, J., Todd, K.J., Lambert, K.A., Robinson, W.A., Van Gulick, R., Weight, R.M., Dart, C.R., and Tobin, R.P. (2020). Simultaneously Inhibiting Bcl2 and Mcl1 Is a Therapeutic Option for Patients with Advanced Melanoma. Cancers, 12.","DOI":"10.3390\/cancers12082182"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"5167","DOI":"10.1038\/s41467-019-12409-w","article-title":"Targeting Melanoma\u2019s MCL1 Bias Unleashes the Apoptotic Potential of BRAF and ERK1\/2 Pathway Inhibitors","volume":"10","author":"Sale","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1038\/s41419-019-1568-3","article-title":"BCL-XL and MCL-1 Are the Key BCL-2 Family Proteins in Melanoma Cell Survival","volume":"10","author":"Lee","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.jid.2018.06.189","article-title":"MicroRNA-211 Loss Promotes Metabolic Vulnerability and BRAF Inhibitor Sensitivity in Melanoma","volume":"139","author":"Sahoo","year":"2019","journal-title":"J. Investig. Dermatol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.jid.2020.06.038","article-title":"MicroRNA-211 Modulates the DUSP6-ERK5 Signaling Axis to Promote BRAFV600E-Driven Melanoma Growth In Vivo and BRAF\/MEK Inhibitor Resistance","volume":"141","author":"Lee","year":"2021","journal-title":"J. Investig. Dermatol."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Ray, A., Kunhiraman, H., and Perera, R.J. (2021). The Paradoxical Behavior of MicroRNA-211 in Melanomas and Other Human Cancers. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.628367"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2487","DOI":"10.7150\/jca.18824","article-title":"Upregulation of Serum MiR-10b Is Associated with Poor Prognosis in Patients with Melanoma","volume":"8","author":"Bai","year":"2017","journal-title":"J. Cancer"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/modpathol.2015.149","article-title":"MicroRNA-10b Is a Prognostic Biomarker for Melanoma","volume":"29","author":"Saldanha","year":"2016","journal-title":"Mod. Pathol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/j.ccell.2015.08.001","article-title":"BRAF Mutants Evade ERK-Dependent Feedback by Different Mechanisms That Determine Their Sensitivity to Pharmacologic Inhibition","volume":"28","author":"Yao","year":"2015","journal-title":"Cancer Cell"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1158\/2159-8290.CD-13-0631","article-title":"MAP Kinase Pathway Alterations in BRAF -Mutant Melanoma Patients with Acquired Resistance to Combined RAF\/MEK Inhibition","volume":"4","author":"Wagle","year":"2014","journal-title":"Cancer Discov."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Pietrobono, S., De Paolo, R., Mangiameli, D., Marranci, A., Battisti, I., Franchin, C., Arrigoni, G., Melisi, D., Poliseno, L., and Stecca, B. (2022). P38 MAPK-Dependent Phosphorylation of Transcription Factor SOX2 Promotes an Adaptive Response to BRAF Inhibitors in Melanoma Cells. J. Biol. Chem., 298.","DOI":"10.1016\/j.jbc.2022.102353"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Czyz, M., and Holzmann, K. (2019). Fibroblast Growth Factor Receptor Signaling in Skin Cancers. Cells, 8.","DOI":"10.3390\/cells8060540"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"5276","DOI":"10.1128\/MCB.16.10.5276","article-title":"A Hierarchical Network of Interreceptor Interactions Determines Signal Transduction by Neu Differentiation Factor\/Neuregulin and Epidermal Growth Factor","volume":"16","author":"Tzahar","year":"1996","journal-title":"Mol. Cell Biol."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Ruggiero, C.F., Malpicci, D., Fattore, L., Madonna, G., Vanella, V., Mallardo, D., Liguoro, D., Salvati, V., Capone, M., and Bedogni, B. (2019). ErbB3 Phosphorylation as Central Event in Adaptive Resistance to Targeted Therapy in Metastatic Melanoma: Early Detection in CTCs during Therapy and Insights into Regulation by Autocrine Neuregulin. Cancers, 11.","DOI":"10.3390\/cancers11101425"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"172621","DOI":"10.1016\/j.ejphar.2019.172621","article-title":"Drug Resistance of BRAF-Mutant Melanoma: Review of up-to-Date Mechanisms of Action and Promising Targeted Agents","volume":"862","author":"Rossi","year":"2019","journal-title":"Eur. J. Pharmacol."},{"key":"ref_102","first-page":"e1736","article-title":"Cooperative Induction of Receptor Tyrosine Kinases Contributes to Adaptive MAPK Drug Resistance in Melanoma through the PI3K Pathway","volume":"6","author":"Alver","year":"2023","journal-title":"Cancer Rep."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1007\/s00018-014-1791-0","article-title":"MITF in Melanoma: Mechanisms behind Its Expression and Activity","volume":"72","author":"Hartman","year":"2015","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_104","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_105","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1038\/s41392-021-00827-6","article-title":"Signal Pathways of Melanoma and Targeted Therapy","volume":"6","author":"Guo","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1007\/978-1-62703-727-3_10","article-title":"Detecting Mechanisms of Acquired BRAF Inhibitor Resistance in Melanoma","volume":"1102","author":"Lo","year":"2014","journal-title":"Molecular Diagnostics for Melanoma"},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Proietti, I., Skroza, N., Bernardini, N., Tolino, E., Balduzzi, V., Marchesiello, A., Michelini, S., Volpe, S., Mambrin, A., and Mangino, G. (2020). Mechanisms of Acquired BRAF Inhibitor Resistance in Melanoma: A Systematic Review. Cancers, 12.","DOI":"10.3390\/cancers12102801"},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Zhai, Z., Vaddi, P.K., Samson, J.M., Takegami, T., and Fujita, M. (2020). NLRP1 Functions Downstream of the MAPK\/ERK Signaling via ATF4 and Contributes to Acquired Targeted Therapy Resistance in Human Metastatic Melanoma. Pharmaceuticals, 14.","DOI":"10.3390\/ph14010023"},{"key":"ref_109","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_110","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1158\/0008-5472.CAN-11-1875","article-title":"Resistance to Selective BRAF Inhibition Can Be Mediated by Modest Upstream Pathway Activation","volume":"72","author":"Su","year":"2012","journal-title":"Cancer Res."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"112696","DOI":"10.1016\/j.celrep.2023.112696","article-title":"Single-Cell Transcriptomics of NRAS-Mutated Melanoma Transitioning to Drug Resistance Reveals P2RX7 as an Indicator of Early Drug Response","volume":"42","author":"Randic","year":"2023","journal-title":"Cell Rep."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1818","DOI":"10.1021\/jm501667n","article-title":"Structural Investigation of B-Raf Paradox Breaker and Inducer Inhibitors","volume":"58","author":"Arora","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"2911","DOI":"10.21873\/anticanres.15773","article-title":"Potent Imidazothiazole-Based Inhibitor of BRAF V600E Overcomes Acquired Resistance via Inhibition of RAF Dimerization in PLX4032-Resistant Melanoma","volume":"42","author":"Poudel","year":"2022","journal-title":"Anticancer. Res."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"114048","DOI":"10.1016\/j.celrep.2024.114048","article-title":"Genomic Deletions Explain the Generation of Alternative BRAF Isoforms Conferring Resistance to MAPK Inhibitors in Melanoma","volume":"43","author":"Aya","year":"2024","journal-title":"Cell Rep."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"ra84","DOI":"10.1126\/scisignal.2001148","article-title":"BRAF Gene Amplification Can Promote Acquired Resistance to MEK Inhibitors in Cancer Cells Harboring the BRAF V600E Mutation","volume":"3","author":"Corcoran","year":"2010","journal-title":"Sci. Signal"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"20411","DOI":"10.1073\/pnas.0905833106","article-title":"MEK1 Mutations Confer Resistance to MEK and B-RAF Inhibition","volume":"106","author":"Emery","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1016\/j.celrep.2013.08.023","article-title":"Concurrent MEK2 Mutation and BRAF Amplification Confer Resistance to BRAF and MEK Inhibitors in Melanoma","volume":"4","author":"Villanueva","year":"2013","journal-title":"Cell Rep."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1038\/nature22071","article-title":"Whole-Genome Landscapes of Major Melanoma Subtypes","volume":"545","author":"Hayward","year":"2017","journal-title":"Nature"},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Tufail, M., Wan, W.D., Jiang, C., and Li, N. (2024). Targeting PI3K\/AKT\/MTOR Signaling to Overcome Drug Resistance in Cancer. Chem. Biol. Interact., 396.","DOI":"10.1016\/j.cbi.2024.111055"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1038\/nm.4155","article-title":"Loss of Cohesin Complex Components STAG2 or STAG3 Confers Resistance to BRAF Inhibition in Melanoma","volume":"22","author":"Shen","year":"2016","journal-title":"Nat. Med."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1007\/164_2017_17","article-title":"Mechanisms of Drug Resistance in Melanoma","volume":"249","author":"Winder","year":"2018","journal-title":"Handbook of Experimental Pharmacology"},{"key":"ref_122","doi-asserted-by":"crossref","unstructured":"Singh, M.K., Altameemi, S., Lares, M., Newton, M.A., and Setaluri, V. (2022). Role of Dual Specificity Phosphatases (DUSPs) in Melanoma Cellular Plasticity and Drug Resistance. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-18578-x"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.1016\/j.celrep.2015.04.049","article-title":"Downregulation of the Ubiquitin Ligase RNF125 Underlies Resistance of Melanoma Cells to BRAF Inhibitors via JAK1 Deregulation","volume":"11","author":"Kim","year":"2015","journal-title":"Cell Rep."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1158\/2159-8290.CD-13-1007","article-title":"The Immune Microenvironment Confers Resistance to MAPK Pathway Inhibitors through Macrophage-Derived TNF","volume":"4","author":"Smith","year":"2014","journal-title":"Cancer Discov."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1158\/1078-0432.CCR-12-1630","article-title":"BRAF Inhibition Is Associated with Enhanced Melanoma Antigen Expression and a More Favorable Tumor Microenvironment in Patients with Metastatic Melanoma","volume":"19","author":"Frederick","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1007\/s11912-016-0531-z","article-title":"Influences of BRAF Inhibitors on the Immune Microenvironment and the Rationale for Combined Molecular and Immune Targeted Therapy","volume":"18","author":"Reddy","year":"2016","journal-title":"Curr. Oncol. Rep."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1080\/08923970802626276","article-title":"The Inhibition of JNK and P38 MAPKs Downregulates IL-10 and Differentially Affects c-Jun Gene Expression in Human Monocytes","volume":"31","author":"Dobreva","year":"2009","journal-title":"Immunopharmacol. Immunotoxicol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1158\/1078-0432.CCR-12-1626","article-title":"BRAF Inhibition Increases Tumor Infiltration by T Cells and Enhances the Antitumor Activity of Adoptive Immunotherapy in Mice","volume":"19","author":"Liu","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1084\/jem.20051848","article-title":"The BRAF-MAPK Signaling Pathway Is Essential for Cancer-Immune Evasion in Human Melanoma Cells","volume":"203","author":"Sumimoto","year":"2006","journal-title":"J. Exp. Med."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1158\/2326-6066.CIR-15-0030","article-title":"BRAFV600E Co-Opts a Conserved MHC Class I Internalization Pathway to Diminish Antigen Presentation and CD8+ T-Cell Recognition of Melanoma","volume":"3","author":"Bradley","year":"2015","journal-title":"Cancer Immunol. Res."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"2769","DOI":"10.1158\/1535-7163.MCT-14-0290","article-title":"Effects of BRAF Mutations and BRAF Inhibition on Immune Responses to Melanoma","volume":"13","author":"Ilieva","year":"2014","journal-title":"Mol. Cancer Ther."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1386","DOI":"10.1158\/1078-0432.CCR-11-2479","article-title":"Selective BRAF Inhibitors Induce Marked T-Cell Infiltration into Human Metastatic Melanoma","volume":"18","author":"Wilmott","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1158\/2326-6066.CIR-13-0215","article-title":"Responseto BRAF Inhibitionin Melanoma Is Enhanced When Combined with Immune Checkpoint Blockade","volume":"2","author":"Cooper","year":"2014","journal-title":"Cancer Immunol. Res."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1007\/s00262-012-1389-z","article-title":"Inhibition of Both BRAF and MEK in BRAFV600E Mutant Melanoma Restores Compromised Dendritic Cell (DC) Function While Having Differential Direct Effects on DC Properties","volume":"62","author":"Ott","year":"2013","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"7298","DOI":"10.1158\/0008-5472.CAN-14-1339","article-title":"Natural Killer Cells Are Essential for the Ability of BRAF Inhibitors to Control BRAFV600E-Mutant Metastatic Melanoma","volume":"74","author":"Ngiow","year":"2014","journal-title":"Cancer Res."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"5329","DOI":"10.1158\/1078-0432.CCR-12-1632","article-title":"Oncogenic BRAF(V600E) Promotes Stromal Cell-Mediated Immunosuppression via Induction of Interleukin-1 in Melanoma","volume":"18","author":"Khalili","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"e25474","DOI":"10.4161\/onci.25474","article-title":"A Role for CCL2 in Both Tumor Progression and Immunosurveillance","volume":"2","author":"Li","year":"2013","journal-title":"Oncoimmunology"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/S1471-4906(02)02302-5","article-title":"Macrophage Polarization: Tumor-Associated Macrophages as a Paradigm for Polarized M2 Mononuclear Phagocytes","volume":"23","author":"Mantovani","year":"2002","journal-title":"Trends Immunol."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1038\/nri2448","article-title":"Exploring the Full Spectrum of Macrophage Activation","volume":"8","author":"Mosser","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1158\/1078-0432.CCR-12-2731","article-title":"The Activation of MAPK in Melanoma Cells Resistant to BRAF Inhibition Promotes PD-L1 Expression That Is Reversible by MEK and PI3K Inhibition","volume":"19","author":"Jiang","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1126\/science.1160809","article-title":"Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation","volume":"324","author":"Heiden","year":"2009","journal-title":"Science"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1007\/s10555-021-09960-8","article-title":"Rethinking the Biology of Metastatic Melanoma: A Holistic Approach","volume":"40","author":"Vandyck","year":"2021","journal-title":"Cancer Metastasis Rev."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"e920957","DOI":"10.12659\/MSM.920957","article-title":"A Review of the Molecular Pathways Involved in Resistance to BRAF Inhibitors in Patients with Advanced-Stage Melanoma","volume":"26","author":"Tian","year":"2020","journal-title":"Med. Sci. Monit."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/j.ccr.2012.11.020","article-title":"PGC1\u03b1 Expression Defines a Subset of Human Melanoma Tumors with Increased Mitochondrial Capacity and Resistance to Oxidative Stress","volume":"23","author":"Vazquez","year":"2013","journal-title":"Cancer Cell"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1038\/s41467-022-28705-x","article-title":"Adaptive Translational Reprogramming of Metabolism Limits the Response to Targeted Therapy in BRAFV600 Melanoma","volume":"13","author":"Smith","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_146","doi-asserted-by":"crossref","unstructured":"Santiappillai, N.T., Abuhammad, S., Slater, A., Kirby, L., McArthur, G.A., Sheppard, K.E., and Smith, L.K. (2021). Cdk4\/6 Inhibition Reprograms Mitochondrial Metabolism in Brafv600 Melanoma via a P53 Dependent Pathway. Cancers, 13.","DOI":"10.3390\/cancers13030524"},{"key":"ref_147","doi-asserted-by":"crossref","unstructured":"Soumoy, L., Schepkens, C., Krayem, M., Najem, A., Tagliatti, V., Ghanem, G.E., Saussez, S., Colet, J.M., and Journe, F. (2020). Metabolic Reprogramming in Metastatic Melanoma with Acquired Resistance to Targeted Therapies: Integrative Metabolomic and Proteomic Analysis. Cancers, 12.","DOI":"10.3390\/cancers12051323"},{"key":"ref_148","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_149","doi-asserted-by":"crossref","first-page":"7008","DOI":"10.1038\/s41467-021-26572-6","article-title":"Intermittent BRAF Inhibition in Advanced BRAF Mutated Melanoma Results of a Phase II Randomized Trial","volume":"12","author":"Oramas","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1038\/s41591-020-1060-8","article-title":"Continuous versus Intermittent BRAF and MEK Inhibition in Patients with BRAF-Mutated Melanoma: A Randomized Phase 2 Trial","volume":"26","author":"Algazi","year":"2020","journal-title":"Nat. Med."},{"key":"ref_151","first-page":"279ra41","article-title":"Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma","volume":"7","author":"Mok","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"5213","DOI":"10.1158\/0008-5472.CAN-10-0118","article-title":"Selective BRAFV600E Inhibition Enhances T-Cell Recognition of Melanoma without Affecting Lymphocyte Function","volume":"70","author":"Boni","year":"2010","journal-title":"Cancer Res."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"1957","DOI":"10.1001\/jamaoncol.2020.4401","article-title":"Rationale for Immune Checkpoint Inhibitors plus Targeted Therapy in Metastatic Melanoma: A Review","volume":"6","author":"Dummer","year":"2020","journal-title":"JAMA Oncol."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1056\/NEJMc1302338","article-title":"Hepatotoxicity with Combination of Vemurafenib and Ipilimumab","volume":"368","author":"Ribas","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1111\/pcmr.12383","article-title":"Severe Gastrointestinal Toxicity with Administration of Trametinib in Combination with Dabrafenib and Ipilimumab","volume":"28","author":"Minor","year":"2015","journal-title":"Pigment Cell Melanoma Res."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"1835","DOI":"10.1016\/S0140-6736(20)30934-X","article-title":"Atezolizumab, Vemurafenib, and Cobimetinib as First-Line Treatment for Unresectable Advanced BRAFV600 Mutation-Positive Melanoma (IMspire150): Primary Analysis of the Randomised, Double-Blind, Placebo-Controlled, Phase 3 Trial","volume":"395","author":"Gutzmer","year":"2020","journal-title":"The Lancet"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"e001806","DOI":"10.1136\/jitc-2020-001806","article-title":"KEYNOTE-022 Part 3: A Randomized, Double-Blind, Phase 2 Study of Pembrolizumab, Dabrafenib, and Trametinib in BRAF-Mutant Melanoma","volume":"8","author":"Ferrucci","year":"2020","journal-title":"J. Immunother. Cancer"},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.1200\/JCO.21.01601","article-title":"Randomized Phase III Trial Evaluating Spartalizumab Plus Dabrafenib and Trametinib for BRAF V600-Mutant Unresectable or Metastatic Melanoma","volume":"40","author":"Dummer","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/S1470-2045(22)00687-8","article-title":"Overall Survival with First-Line Atezolizumab in Combination with Vemurafenib and Cobimetinib in BRAFV600 Mutation-Positive Advanced Melanoma (IMspire150): Second Interim Analysis of a Multicentre, Randomised, Phase 3 Study","volume":"24","author":"Ascierto","year":"2023","journal-title":"Lancet Oncol."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1158\/1535-7163.MCT-13-0481","article-title":"Overcoming Acquired BRAF Inhibitor Resistance in Melanoma via Targeted Inhibition of Hsp90 with Ganetespib","volume":"13","author":"Acquaviva","year":"2014","journal-title":"Mol. Cancer Ther."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s41231-022-00133-5","article-title":"Targeting EphA2 and DDR Signaling Can Overcome the BRAF and MEK Inhibitors Acquired Resistance in Melanoma Cell Lines","volume":"8","author":"Belli","year":"2023","journal-title":"Transl. Med. Commun."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"521","DOI":"10.2147\/JEP.S297831","article-title":"Combinatorial Therapies to Overcome Braf\/Mek Inhibitors Resistance in Melanoma Cells: An in Vitro Study","volume":"13","author":"Domingues","year":"2021","journal-title":"J. Exp. Pharmacol."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/s41698-021-00190-3","article-title":"Overcoming Resistance to BRAFV600E Inhibition in Melanoma by Deciphering and Targeting Personalized Protein Network Alterations","volume":"5","author":"Vasudevan","year":"2021","journal-title":"NPJ Precis. Oncol."},{"key":"ref_164","doi-asserted-by":"crossref","unstructured":"Colakoglu Bergel, C., Eryilmaz, I.E., Cecener, G., and Egeli, U. (2025). Second-Generation BRAF Inhibitor Encorafenib Resistance Is Regulated by NCOA4-Mediated Iron Trafficking in the Drug-Resistant Malignant Melanoma Cells. Sci. Rep., 15.","DOI":"10.1038\/s41598-025-86874-3"},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"108200","DOI":"10.1016\/j.pharmthera.2022.108200","article-title":"The Future of Targeted Kinase Inhibitors in Melanoma","volume":"239","author":"Caksa","year":"2022","journal-title":"Pharmacol. Ther."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1002\/mc.23253","article-title":"Mcl-1 Targeting Strategies Unlock the Proapoptotic Potential of TRAIL in Melanoma Cells","volume":"59","author":"Sarif","year":"2020","journal-title":"Mol. Carcinog."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"102778","DOI":"10.1016\/j.nano.2024.102778","article-title":"Robust Aptamer-Targeted CRISPR\/Cas9 Delivery Using Mesenchymal Stem Cell Membrane \u2013Liposome Hybrid: BIRC5 Gene Knockout against Melanoma","volume":"62","author":"Ghaemi","year":"2024","journal-title":"Nanomedicine"},{"key":"ref_168","doi-asserted-by":"crossref","unstructured":"Moras, B., and Sissi, C. (2025). Unravelling the Regulatory Roles of LncRNAs in Melanoma: From Mechanistic Insights to Target Selection. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26052126"},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"1784","DOI":"10.1002\/cncr.35200","article-title":"A Phase 1 Study of Triple-Targeted Therapy with BRAF, MEK, and AKT Inhibitors for Patients with BRAF-Mutated Cancers","volume":"130","author":"Algazi","year":"2024","journal-title":"Cancer"},{"key":"ref_170","doi-asserted-by":"crossref","unstructured":"Castellani, G., Buccarelli, M., Arasi, M.B., Rossi, S., Pisanu, M.E., Bellenghi, M., Lintas, C., and Tabolacci, C. (2023). BRAF Mutations in Melanoma: Biological Aspects, Therapeutic Implications, and Circulating Biomarkers. Cancers, 15.","DOI":"10.3390\/cancers15164026"},{"key":"ref_171","first-page":"211","article-title":"The Evolution of BRAF-Targeted Therapies in Melanoma: Overcoming Hurdles and Unleashing Novel Strategies","volume":"130","author":"Imani","year":"2024","journal-title":"Cancer Rev."},{"key":"ref_172","doi-asserted-by":"crossref","unstructured":"Marsavela, G., Johansson, P.A., Pereira, M.R., McEvoy, A.C., Reid, A.L., Robinson, C., Warburton, L., Khattak, M.A., Meniawy, T.M., and Amanuel, B. (2020). The Prognostic Impact of Circulating Tumour Dna in Melanoma Patients Treated with Systemic Therapies\u2014Beyond Braf Mutant Detection. Cancers, 12.","DOI":"10.3390\/cancers12123793"},{"key":"ref_173","doi-asserted-by":"crossref","unstructured":"Welti, M., Dimitriou, F., Gutzmer, R., and Dummer, R. (2022). Triple Combination of Immune Checkpoint Inhibitors and BRAF\/MEK Inhibitors in BRAFV600 Melanoma: Current Status and Future Perspectives. Cancers, 14.","DOI":"10.3390\/cancers14225489"},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1038\/s41698-024-00567-0","article-title":"A Multiparameter Liquid Biopsy Approach Allows to Track Melanoma Dynamics and Identify Early Treatment Resistance","volume":"8","author":"Scaini","year":"2024","journal-title":"NPJ Precis. Oncol."},{"key":"ref_175","doi-asserted-by":"crossref","unstructured":"Krebs, F.S., Moura, B., Missiaglia, E., Aedo-Lopez, V., Michielin, O., Tsantoulis, P., Bisig, B., Trimech, M., Zoete, V., and Homicsko, K. (2023). Response and Resistance to Trametinib in MAP2K1-Mutant Triple-Negative Melanoma. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24054520"},{"key":"ref_176","doi-asserted-by":"crossref","unstructured":"Padovano, F., and Villa, C. (2024). The Development of Drug Resistance in Metastatic Tumours under Chemotherapy: An Evolutionary Perspective. J. Theor. Biol., 595.","DOI":"10.1016\/j.jtbi.2024.111957"},{"key":"ref_177","doi-asserted-by":"crossref","unstructured":"Taghizadeh, R., Noh, M., Huh, Y.H., Ciusani, E., Sigalotti, L., Maio, M., Arosio, B., Nicotra, M.R., Natali, P., and Sherley, J.L. (2010). Cxcr6, a Newly Defined Biomarker of Tissue-Specific Stem Cell Asymmetric Self-Renewal, Identifies More Aggressive Human Melanoma Cancer Stem Cells. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0015183"},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1007\/s00432-024-05957-2","article-title":"Melanoma Genomics\u2014Will We Go beyond BRAF in Clinics?","volume":"150","author":"Mirek","year":"2024","journal-title":"Cancer Res. Clin. Oncol."},{"key":"ref_179","doi-asserted-by":"crossref","unstructured":"Sobczuk, P., Kozak, K., Kope\u0107, S., Rogala, P., \u015awitaj, T., Kose\u0142a-Paterczyk, H., Gos, A., Tysarowski, A., and Rutkowski, P. (2022). The Use of CtDNA for BRAF Mutation Testing in Routine Clinical Practice in Patients with Advanced Melanoma. Cancers, 14.","DOI":"10.3390\/cancers14030777"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/8\/1235\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:32:46Z","timestamp":1760034766000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/8\/1235"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,21]]},"references-count":179,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["ph18081235"],"URL":"https:\/\/doi.org\/10.3390\/ph18081235","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,21]]}}}