{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T18:07:00Z","timestamp":1792951620114,"version":"4.5.0"},"reference-count":77,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,8,26]],"date-time":"2022-08-26T00:00:00Z","timestamp":1661472000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81773752 22105137"],"award-info":[{"award-number":["81773752 22105137"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2020M683324"],"award-info":[{"award-number":["2020M683324"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Immune checkpoint blockade and MAPK-targeted combined therapy is a promising regimen for advanced melanoma patients. However, the clinical benefit from this combo regimen remains limited, especially in patients who acquired resistance to MAPK-targeted therapy. Here, we systematically characterized the immune landscape during MAPK-targeted therapy in patients and mouse melanoma models. We observed that both the abundance of tumor-infiltrated T cells and the expression of immune-related genes were upregulated in the drug-responsive period, but downregulated in the resistance period, implying that acquired drug resistance dampens the antitumor immune response. Further transcriptomic dissection indicated that loss of MHC-I antigen presentation on tumor cells plays a critical role in the reduction of T cell infiltration during drug resistance. Survival analysis demonstrates that loss of antigen presentation and reduction of T-cell infiltration during acquired drug resistance are associated with poorer clinical response and prognosis of anti-PD-1 therapy in melanoma patients. In addition, we identified that alterations in the MAPK inhibitor resistance-related oncogenic signaling pathway closely correlated with deficiency of MHC-I antigen presentation, including activation of the PI3K-mTOR, MAPK, and Wnt pathways. In conclusion, our research illuminates that decreased infiltration of T cells is associated with acquired drug resistance during MAPK-targeted therapy, which may underlie the cross-resistance to immune checkpoint blockade.<\/jats:p>","DOI":"10.3389\/fphar.2022.928226","type":"journal-article","created":{"date-parts":[[2022,8,26]],"date-time":"2022-08-26T04:30:56Z","timestamp":1661488256000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":25,"title":["Loss of MHC-I antigen presentation correlated with immune checkpoint blockade tolerance in MAPK inhibitor-resistant melanoma"],"prefix":"10.3389","volume":"13","author":[{"given":"Jing","family":"Yu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinen","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujie","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huifang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowei","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,8,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1186\/s12885-018-4618-9","article-title":"Ineffective anti PD-1 therapy after BRAF inhibitor failure in advanced melanoma","volume":"18","author":"Amini-Adle","year":"2018","journal-title":"BMC Cancer"},{"key":"B2","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1186\/1479-5876-10-85","article-title":"The role of BRAF V600 mutation in melanoma","volume":"10","author":"Ascierto","year":"2012","journal-title":"J. Transl. Med."},{"key":"B3","doi-asserted-by":"publisher","first-page":"793831","DOI":"10.3389\/fimmu.2021.793831","article-title":"Improvement of PD-1 blockade efficacy and elimination of immune-related gastrointestinal adverse effect by mTOR inhibitor","volume":"12","author":"Bai","year":"2021","journal-title":"Front. Immunol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1186\/s13059-016-1070-5","article-title":"Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression","volume":"17","author":"Becht","year":"2016","journal-title":"Genome Biol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1052","DOI":"10.1182\/blood-2011-03-340109","article-title":"The novel anti-MEK small molecule AZD6244 induces BIM-dependent and AKT-independent apoptosis in diffuse large B-cell lymphoma","volume":"118","author":"Bhalla","year":"2011","journal-title":"Blood"},{"key":"B6","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1038\/nature09454","article-title":"Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma","volume":"467","author":"Bollag","year":"2010","journal-title":"Nature"},{"key":"B7","doi-asserted-by":"publisher","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":"B8","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1038\/nbt.3519","article-title":"Near-optimal probabilistic RNA-seq quantification","volume":"34","author":"Bray","year":"2016","journal-title":"Nat. Biotechnol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"936","DOI":"10.1158\/2326-6066.Cir-16-0177","article-title":"Kinase regulation of human MHC class I molecule expression on cancer cells","volume":"4","author":"Brea","year":"2016","journal-title":"Cancer Immunol. Res."},{"key":"B10","doi-asserted-by":"publisher","first-page":"2971","DOI":"10.4049\/jimmunol.1600460","article-title":"Cell signaling pathways that regulate antigen presentation","volume":"197","author":"Brutkiewicz","year":"2016","journal-title":"J. Immunol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"3446","DOI":"10.1002\/cncr.28864","article-title":"The MAPK pathway across different malignancies: A new perspective","volume":"120","author":"Burotto","year":"2014","journal-title":"Cancer"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1002","DOI":"10.1016\/s0140-6736(21)01206-x","article-title":"Immune checkpoint inhibitors in melanoma","volume":"398","author":"Carlino","year":"2021","journal-title":"Lancet"},{"key":"B13","doi-asserted-by":"publisher","first-page":"2395","DOI":"10.1158\/1541-7786.Mcr-19-0545","article-title":"Phosphoinositide 3-kinase signaling can modulate MHC class I and II expression","volume":"17","author":"Chandrasekaran","year":"2019","journal-title":"Mol. Cancer Res."},{"key":"B14","doi-asserted-by":"publisher","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":"B15","doi-asserted-by":"publisher","first-page":"E1760","DOI":"10.3390\/cancers12071760","article-title":"MHC class I downregulation in cancer: Underlying mechanisms and potential targets for cancer immunotherapy","volume":"12","author":"Cornel","year":"2020","journal-title":"Cancers (Basel)"},{"key":"B16","doi-asserted-by":"publisher","first-page":"e1238557","DOI":"10.1080\/2162402x.2016.1238557","article-title":"Targeting the MAPK and PI3K pathways in combination with PD1 blockade in melanoma","volume":"5","author":"Deken","year":"2016","journal-title":"Oncoimmunology"},{"key":"B17","doi-asserted-by":"publisher","first-page":"636568","DOI":"10.3389\/fimmu.2021.636568","article-title":"Cancer immune evasion through loss of MHC class I antigen presentation","volume":"12","author":"Dhatchinamoorthy","year":"2021","journal-title":"Front. Immunol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1016\/j.ygyno.2021.09.026","article-title":"Sequential modulation of the Wnt\/\u03b2-catenin signaling pathway enhances tumor-intrinsic MHC I expression and tumor clearance","volume":"164","author":"Dholakia","year":"2022","journal-title":"Gynecol. Oncol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1428","DOI":"10.1200\/jco.21.01601","article-title":"Randomized phase III trial evaluating spartalizumab plus dabrafenib and trametinib for BRAF V600\u2013mutant unresectable or metastatic melanoma","volume":"21","author":"Dummer","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1177\/1758834015616934","article-title":"Combination therapy with BRAF and MEK inhibitors for melanoma: Latest evidence and place in therapy","volume":"8","author":"Eroglu","year":"2016","journal-title":"Ther. Adv. Med. Oncol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1038\/s41591-019-0734-6","article-title":"Peripheral CD8(+) T cell characteristics associated with durable responses to immune checkpoint blockade in patients with metastatic melanoma","volume":"26","author":"Fairfax","year":"2020","journal-title":"Nat. Med."},{"key":"B22","doi-asserted-by":"publisher","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.for ImmunoTherapy of cancer","volume":"8","author":"Ferrucci","year":"2020","journal-title":"J. Immunother. Cancer"},{"key":"B23","doi-asserted-by":"publisher","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":"B24","doi-asserted-by":"publisher","first-page":"603","DOI":"10.20517\/cdr.2019.109","article-title":"MEK inhibition activates STAT signaling to increase breast cancer immunogenicity via MHC-I expression","volume":"3","author":"Franklin","year":"2020","journal-title":"Cancer Drug resist."},{"key":"B25","doi-asserted-by":"publisher","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":"B26","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1016\/j.ccell.2019.01.003","article-title":"Distinct immune cell populations define response to anti-PD-1 monotherapy and anti-PD-1\/anti-CTLA-4 combined therapy","volume":"35","author":"Gide","year":"2019","journal-title":"Cancer Cell"},{"key":"B27","doi-asserted-by":"publisher","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":"Lancet"},{"key":"B28","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1016\/j.ccr.2014.07.007","article-title":"Structure of the BRAF-MEK complex reveals a kinase activity independent role for BRAF in MAPK signaling","volume":"26","author":"Haling","year":"2014","journal-title":"Cancer Cell"},{"key":"B29","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1016\/j.ejca.2021.08.013","article-title":"Long-term outcomes in patients with advanced melanoma who had initial stable disease with pembrolizumab in KEYNOTE-001 and KEYNOTE-006","volume":"157","author":"Hamid","year":"2021","journal-title":"Eur. J. Cancer"},{"key":"B30","doi-asserted-by":"publisher","first-page":"9010","DOI":"10.1200\/jco.2013.31.15_suppl.9010","article-title":"Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic melanoma (mM)","volume":"31","author":"Hamid","year":"2013","journal-title":"J. Clin. Oncol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/1471-2105-14-7","article-title":"Gsva: Gene set variation analysis for microarray and RNA-seq data","volume":"14","author":"H\u00e4nzelmann","year":"2013","journal-title":"BMC Bioinforma."},{"key":"B32","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.intimp.2018.06.001","article-title":"Immune checkpoint blockade therapy for cancer: An overview of FDA-approved immune checkpoint inhibitors","volume":"62","author":"Hargadon","year":"2018","journal-title":"Int. Immunopharmacol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1016\/S0140-6736(12)60868-X","article-title":"Dabrafenib in BRAF-mutated metastatic melanoma: A multicentre, open-label, phase 3 randomised controlled trial","volume":"380","author":"Hauschild","year":"2012","journal-title":"Lancet"},{"key":"B34","doi-asserted-by":"publisher","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":"B35","doi-asserted-by":"publisher","first-page":"279ra41","DOI":"10.1126\/scitranslmed.aaa4691","article-title":"Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma","volume":"7","author":"Hu-Lieskovan","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"B36","doi-asserted-by":"publisher","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":"B37","doi-asserted-by":"publisher","first-page":"542","DOI":"10.1016\/j.cell.2017.01.010","article-title":"Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma","volume":"168","author":"Hugo","year":"2017","journal-title":"Cell"},{"key":"B38","doi-asserted-by":"publisher","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":"B39","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/j.molimm.2021.05.009","article-title":"Playing hide and seek: Tumor cells in control of MHC class I antigen presentation","volume":"136","author":"Jongsma","year":"2021","journal-title":"Mol. Immunol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"1371","DOI":"10.1172\/jci66236","article-title":"Host immunity contributes to the anti-melanoma activity of BRAF inhibitors","volume":"123","author":"Knight","year":"2013","journal-title":"J. Clin. Invest."},{"key":"B41","doi-asserted-by":"publisher","first-page":"3928","DOI":"10.1158\/0008-5472.Can-11-2837","article-title":"BRAF inhibitor vemurafenib improves the antitumor activity of adoptive cell immunotherapy","volume":"72","author":"Koya","year":"2012","journal-title":"Cancer Res."},{"key":"B42","doi-asserted-by":"publisher","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":"B43","doi-asserted-by":"publisher","first-page":"1459","DOI":"10.1172\/jci78954","article-title":"Co-clinical assessment identifies patterns of BRAF inhibitor resistance in melanoma","volume":"125","author":"Kwong","year":"2015","journal-title":"J. Clin. Invest."},{"key":"B44","doi-asserted-by":"publisher","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":"B45","doi-asserted-by":"publisher","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":"B46","doi-asserted-by":"publisher","first-page":"1739","DOI":"10.1093\/bioinformatics\/btr260","article-title":"Molecular signatures database (MSigDB) 3.0","volume":"27","author":"Liberzon","year":"2011","journal-title":"Bioinformatics"},{"key":"B47","doi-asserted-by":"publisher","first-page":"1806916","DOI":"10.1002\/adfm.201806916","article-title":"MAPK\u2010Targeted drug delivered by a pH\u2010sensitive MSNP nanocarrier synergizes with PD\u20101 blockade in melanoma without T\u2010cell suppression","volume":"29","author":"Liu","year":"2019","journal-title":"Adv. Funct. Mat."},{"key":"B48","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1016\/j.jconrel.2021.02.020","article-title":"Combination of MAPK inhibition with photothermal therapy synergistically augments the anti-tumor efficacy of immune checkpoint blockade","volume":"332","author":"Liu","year":"2021","journal-title":"J. Control. Release"},{"key":"B49","doi-asserted-by":"publisher","first-page":"1499","DOI":"10.1158\/1078-0432.Ccr-15-1125","article-title":"RAS\/MAPK activation is associated with reduced tumor-infiltrating lymphocytes in triple-negative breast cancer: Therapeutic cooperation between MEK and PD-1\/PD-L1 immune checkpoint inhibitors","volume":"22","author":"Loi","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"B50","doi-asserted-by":"publisher","first-page":"2416","DOI":"10.1038\/s41418-019-0310-0","article-title":"Therapeutic resistance and susceptibility is shaped by cooperative multi-compartment tumor adaptation","volume":"26","author":"Long","year":"2019","journal-title":"Cell Death Differ."},{"key":"B51","doi-asserted-by":"publisher","first-page":"268","DOI":"10.3389\/fonc.2019.00268","article-title":"Diverse mechanisms of BRAF inhibitor resistance in melanoma identified in clinical and preclinical studies","volume":"9","author":"Luebker","year":"2019","journal-title":"Front. Onco"},{"key":"B52","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1038\/nri3084","article-title":"Towards a systems understanding of MHC class I and MHC class II antigen presentation","volume":"11","author":"Neefjes","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1186\/s13073-020-00783-w","article-title":"The murine Microenvironment Cell Population counter method to estimate abundance of tissue-infiltrating immune and stromal cell populations in murine samples using gene expression","volume":"12","author":"Petitprez","year":"2020","journal-title":"Genome Med."},{"key":"B54","doi-asserted-by":"publisher","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":"B55","doi-asserted-by":"publisher","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"Limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"B56","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1016\/j.ejca.2020.11.010","article-title":"Long-term safety of pembrolizumab monotherapy and relationship with clinical outcome: A landmark analysis in patients with advanced melanoma","volume":"144","author":"Robert","year":"2021","journal-title":"Eur. J. Cancer"},{"key":"B57","doi-asserted-by":"publisher","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":"B58","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.phrs.2019.03.006","article-title":"Properties of FDA-approved small molecule protein kinase inhibitors","volume":"144","author":"Roskoski","year":"2019","journal-title":"Pharmacol. Res."},{"key":"B59","doi-asserted-by":"publisher","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":"B60","doi-asserted-by":"publisher","first-page":"1136","DOI":"10.1038\/s41467-017-01062-w","article-title":"Resistance to checkpoint blockade therapy through inactivation of antigen presentation","volume":"8","author":"Sade-Feldman","year":"2017","journal-title":"Nat. Commun."},{"key":"B61","doi-asserted-by":"publisher","first-page":"321321","DOI":"10.1016\/j.cell.2018.03.035","article-title":"Oncogenic signaling pathways in the cancer genome atlas","volume":"173","author":"Sanchez-Vega","year":"2018","journal-title":"Cell"},{"key":"B62","doi-asserted-by":"publisher","first-page":"e22890","DOI":"10.4161\/onci.22890","article-title":"Vemurafenib enhances MHC induction in BRAF(V600E) homozygous melanoma cells","volume":"2","author":"Sapkota","year":"2013","journal-title":"Oncoimmunology"},{"key":"B63","doi-asserted-by":"publisher","first-page":"3374","DOI":"10.3390\/cancers12113374","article-title":"Tumor MHC expression guides first-line immunotherapy selection in melanoma","volume":"12","author":"Shklovskaya","year":"2020","journal-title":"Cancers"},{"key":"B64","doi-asserted-by":"publisher","first-page":"6741","DOI":"10.3390\/ijms22136741","article-title":"MHC class I deficiency in solid tumors and therapeutic strategies to overcome it","volume":"22","author":"Shklovskaya","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B65","doi-asserted-by":"publisher","first-page":"1248","DOI":"10.1158\/2159-8290.Cd-17-0401","article-title":"Recurrent tumor cell-intrinsic and -extrinsic alterations during MAPKi-induced melanoma regression and early adaptation","volume":"7","author":"Song","year":"2017","journal-title":"Cancer Discov."},{"key":"B66","doi-asserted-by":"publisher","first-page":"18881888","DOI":"10.1016\/j.cell.2019.05.031","article-title":"Comprehensive integration of single-cell data","volume":"177","author":"Stuart","year":"2019","journal-title":"Cell"},{"key":"B67","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1016\/j.trecan.2020.05.009","article-title":"Clinical development of BRAF plus MEK inhibitor combinations","volume":"6","author":"Subbiah","year":"2020","journal-title":"Trends Cancer"},{"key":"B68","doi-asserted-by":"publisher","first-page":"129736","DOI":"10.1016\/j.bbagen.2020.129736","article-title":"Resistance mechanisms to targeted therapy in BRAF-mutant melanoma - a mini review","volume":"1865","author":"Tangella","year":"2021","journal-title":"Biochim. Biophys. Acta. Gen. Subj."},{"key":"B69","doi-asserted-by":"publisher","first-page":"844866","DOI":"10.3389\/fimmu.2022.844866","article-title":"Mechanisms of MHC-I downregulation and role in immunotherapy response","volume":"13","author":"Taylor","year":"2022","journal-title":"Front. Immunol."},{"key":"B70","doi-asserted-by":"publisher","first-page":"1023","DOI":"10.1002\/j.1460-2075.1988.tb02909.x","article-title":"c-myc down-regulates class I HLA expression in human melanomas","volume":"7","author":"Versteeg","year":"1988","journal-title":"EMBO J."},{"key":"B71","doi-asserted-by":"publisher","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":"B72","doi-asserted-by":"publisher","first-page":"100141","DOI":"10.1016\/j.xinn.2021.100141","article-title":"clusterProfiler 4.0: A universal enrichment tool for interpreting omics data","volume":"2","author":"Wu","year":"2021","journal-title":"Innovation."},{"key":"B73","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1016\/j.jid.2021.07.162","article-title":"The evolution of acquired resistance to BRAF(V600E) kinase inhibitor is sustained by IGF1-driven tumor vascular remodeling","volume":"142","author":"Xu","year":"2022","journal-title":"J. Invest. Dermatol."},{"key":"B74","doi-asserted-by":"publisher","first-page":"1098","DOI":"10.1038\/s41388-019-1045-6","article-title":"MHC class I dysfunction of glioma stem cells escapes from CTL-mediated immune response via activation of Wnt\/\u03b2-catenin signaling pathway","volume":"39","author":"Yang","year":"2020","journal-title":"Oncogene"},{"key":"B75","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1186\/s43556-020-00013-0","article-title":"Integrin-Src-YAP1 signaling mediates the melanoma acquired resistance to MAPK and PI3K\/mTOR dual targeted therapy","volume":"1","author":"Yu","year":"2020","journal-title":"Mol. Biomed."},{"key":"B76","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1186\/s13045-020-00949-4","article-title":"The MAPK and AMPK signalings: Interplay and implication in targeted cancer therapy","volume":"13","author":"Yuan","year":"2020","journal-title":"J. Hematol. Oncol."},{"key":"B77","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1038\/s41392-022-00881-8","article-title":"Single-cell transcriptomic profiling unravels the adenoma-initiation role of protein tyrosine kinases during colorectal tumorigenesis","volume":"7","author":"Zheng","year":"2022","journal-title":"Signal Transduct. Target. Ther."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.928226\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,26]],"date-time":"2022-08-26T04:30:59Z","timestamp":1661488259000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.928226\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,26]]},"references-count":77,"alternative-id":["10.3389\/fphar.2022.928226"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2022.928226","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,26]]},"article-number":"928226"}}