{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T18:55:10Z","timestamp":1768589710962,"version":"3.49.0"},"reference-count":46,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2020,10,20]],"date-time":"2020-10-20T00:00:00Z","timestamp":1603152000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,10,20]],"date-time":"2020-10-20T00:00:00Z","timestamp":1603152000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100005984","name":"Dr. Miriam and Sheldon G. Adelson Medical Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005984","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["U54 CA224070 and P01"],"award-info":[{"award-number":["U54 CA224070 and P01"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002794","name":"Cancerfonden","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002794","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007232","name":"Radiumhemmets Forskningsfonder","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007232","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004063","name":"Knut och Alice Wallenbergs Stiftelse","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004063","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Current treatment modalities for disseminated cutaneous malignant melanoma (CMM) improve survival, however disease progression commonly ensues. In a previous study we identified afatinib and crizotinib in combination as a novel potential therapy for CMM independent of <jats:italic>BRAF\/NRAS<\/jats:italic> mutation status. Herein, we elucidate the underlying mechanisms of the combination treatment effect to find biomarkers and novel targets for development of therapy that may provide clinical benefit by proteomic analysis of CMM cell lines and xenografts using mass spectrometry based analysis and reverse phase protein array. Identified candidates were validated using immunoblotting or immunofluorescence. Our analysis revealed that mTOR\/Insulin signaling pathways were significantly decreased by the afatinib and crizotinib combination treatment. Both in vitro and in vivo analyses showed that the combination treatment downregulated pRPS6KB1 and pRPS6, downstream of mTOR signaling, and IRS-1 in the insulin signaling pathway, specifically ablating IRS-1 nuclear signal. Silencing of RPS6 and IRS-1 alone had a similar effect on cell death, which was further induced when IRS-1 and RPS6 were concomitantly silenced in the CMM cell lines. Silencing of IRS-1 and RPS6 resulted in reduced sensitivity towards combination treatment. Additionally, we found that IRS-1 and RPS6KB1 expression levels were increased in advanced stages of CMM clinical samples. We could demonstrate that induced resistance towards combination treatment was reversible by a drug holiday. CD171\/L1CAM, mTOR and PI3K-p85 were induced in the combination resistant cells whereas AXL and EPHA2, previously identified mediators of resistance to MAPK inhibitor therapy in CMM were downregulated. We also found that CD171\/L1CAM and mTOR were increased at progression in tumor biopsies from two matched cases of patients receiving targeted therapy with BRAFi. Overall, these findings provide insights into the molecular mechanisms behind the afatinib and crizotinib combination treatment effect and leverages a platform for discovering novel biomarkers and therapy regimes for CMM treatment.<\/jats:p>","DOI":"10.1038\/s41419-020-03097-2","type":"journal-article","created":{"date-parts":[[2020,10,20]],"date-time":"2020-10-20T12:02:47Z","timestamp":1603195367000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Inhibiting insulin and mTOR signaling by afatinib and crizotinib combination fosters broad cytotoxic effects in cutaneous malignant melanoma"],"prefix":"10.1038","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2019-8072","authenticated-orcid":false,"given":"Ishani","family":"Das","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huiqin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2297-6488","authenticated-orcid":false,"given":"Gianluca","family":"Maddalo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rainer","family":"Tuominen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vito W.","family":"Rebecca","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0839-0739","authenticated-orcid":false,"given":"Meenhard","family":"Herlyn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johan","family":"Hansson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0977-0912","authenticated-orcid":false,"given":"Michael A.","family":"Davies","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0524-2346","authenticated-orcid":false,"given":"Suzanne","family":"Egyh\u00e1zi Brage","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,10,20]]},"reference":[{"key":"3097_CR1","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1200\/EDBK_240837","volume":"39","author":"CM Fares","year":"2019","unstructured":"Fares, C. M., Van Allen, E. M., Drake, C. G., Allison, J. P. & Hu-Lieskovan, S. Mechanisms of resistance to immune checkpoint blockade: why does checkpoint inhibitor immunotherapy not work for all patients? Am. Soc. Clin. Oncol. Educ. Book 39, 147\u2013164 (2019).","journal-title":"Am. Soc. Clin. Oncol. Educ. Book"},{"key":"3097_CR2","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1038\/s41591-019-0474-7","volume":"25","author":"RJ Sullivan","year":"2019","unstructured":"Sullivan, R. J. et al. Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients. Nat. Med. 25, 929\u2013935 (2019).","journal-title":"Nat. Med."},{"key":"3097_CR3","doi-asserted-by":"publisher","first-page":"1535","DOI":"10.1056\/NEJMoa1910836","volume":"381","author":"J Larkin","year":"2019","unstructured":"Larkin, J. et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 381, 1535\u20131546 (2019).","journal-title":"N. Engl. J. Med."},{"key":"3097_CR4","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1016\/S0140-6736(18)31559-9","volume":"392","author":"D Schadendorf","year":"2018","unstructured":"Schadendorf, D. et al. Melanoma. Lancet 392, 971\u2013984 (2018).","journal-title":"Lancet"},{"key":"3097_CR5","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1007\/978-3-319-22539-5_10","volume":"167","author":"DJ Wong","year":"2016","unstructured":"Wong, D. J. & Ribas, A. Targeted therapy for melanoma. Cancer Treat. Res. 167, 251\u2013262 (2016).","journal-title":"Cancer Treat. Res."},{"key":"3097_CR6","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1038\/nrclinonc.2017.43","volume":"14","author":"JJ Luke","year":"2017","unstructured":"Luke, J. J., Flaherty, K. T., Ribas, A. & Long, G. V. Targeted agents and immunotherapies: optimizing outcomes in melanoma. Nat. Rev. Clin. Oncol. 14, 463\u2013482 (2017).","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"3097_CR7","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6712","volume":"5","author":"J Muller","year":"2014","unstructured":"Muller, J. et al. Low MITF\/AXL ratio predicts early resistance to multiple targeted drugs in melanoma. Nat. Commun. 5, 5712 (2014).","journal-title":"Nat. Commun."},{"key":"3097_CR8","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-019-1875-8","volume":"10","author":"I Das","year":"2019","unstructured":"Das, I. et al. Combining ERBB family and MET inhibitors is an effective therapeutic strategy in cutaneous malignant melanoma independent of BRAF\/NRAS mutation status. Cell Death Dis. 10, 663 (2019).","journal-title":"Cell Death Dis."},{"key":"3097_CR9","doi-asserted-by":"publisher","first-page":"1863","DOI":"10.1038\/jid.2015.105","volume":"135","author":"Z Ji","year":"2015","unstructured":"Ji, Z. et al. MITF modulates therapeutic resistance through EGFR signaling. J. Invest. Dermatol. 135, 1863\u20131872 (2015).","journal-title":"J. Invest. Dermatol."},{"key":"3097_CR10","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1200\/JCO.2017.74.1025","volume":"36","author":"GV Long","year":"2018","unstructured":"Long, G. V. et al. Long-term outcomes in patients With BRAF V600\u2013mutant metastatic melanoma who received dabrafenib combined with trametinib. J. Clin. Oncol. 36, 667\u2013673 (2018).","journal-title":"J. Clin. Oncol."},{"key":"3097_CR11","doi-asserted-by":"publisher","first-page":"936","DOI":"10.1038\/s41591-019-0476-5","volume":"25","author":"A Ribas","year":"2019","unstructured":"Ribas, A. et al. Combined BRAF and MEK inhibition with PD-1 blockade immunotherapy in BRAF-mutant melanoma. Nat. Med. 25, 936\u2013940 (2019).","journal-title":"Nat. Med."},{"key":"3097_CR12","doi-asserted-by":"publisher","first-page":"9","DOI":"10.4103\/1477-3163.44372","volume":"7","author":"N Puri","year":"2008","unstructured":"Puri, N. & Salgia, R. Synergism of EGFR and c-Met pathways, cross-talk and inhibition, in non-small cell lung cancer. J. Carcinog. 7, 9 (2008).","journal-title":"J. Carcinog."},{"key":"3097_CR13","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1002\/mc.22342","volume":"55","author":"Y Lee","year":"2016","unstructured":"Lee, Y., Wang, Y., James, M., Jeong, J. H. & You, M. Inhibition of IGF1R signaling abrogates resistance to afatinib (BIBW2992) in EGFR T790M mutant lung cancer cells. Mol. Carcinog. 55, 991\u20131001 (2016).","journal-title":"Mol. Carcinog."},{"key":"3097_CR14","doi-asserted-by":"publisher","first-page":"e84700","DOI":"10.1371\/journal.pone.0084700","volume":"8","author":"S Nanjo","year":"2013","unstructured":"Nanjo, S. et al. Ability of the Met kinase inhibitor crizotinib and new generation EGFR inhibitors to overcome resistance to EGFR inhibitors. PLoS ONE 8, e84700 (2013).","journal-title":"PLoS ONE"},{"key":"3097_CR15","doi-asserted-by":"publisher","first-page":"3895","DOI":"10.1083\/jcb.201710039","volume":"216","author":"A Colaco","year":"2017","unstructured":"Colaco, A. & Jaattela, M. Ragulator-a multifaceted regulator of lysosomal signaling and trafficking. J. Cell Biol. 216, 3895\u20133898 (2017).","journal-title":"J. Cell Biol."},{"key":"3097_CR16","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.ceb.2016.01.006","volume":"39","author":"LA Huber","year":"2016","unstructured":"Huber, L. A. & Teis, D. Lysosomal signaling in control of degradation pathways. Curr. Opin. Cell Biol. 39, 8\u201314 (2016).","journal-title":"Curr. Opin. Cell Biol."},{"key":"3097_CR17","doi-asserted-by":"publisher","first-page":"6425","DOI":"10.1128\/MCB.01254-05","volume":"26","author":"OJ Shah","year":"2006","unstructured":"Shah, O. J. & Hunter, T. Turnover of the active fraction of IRS1 involves raptor-mTOR- and S6K1-dependent serine phosphorylation in cell culture models of tuberous sclerosis. Mol. Cell Biol. 26, 6425\u20136434 (2006).","journal-title":"Mol. Cell Biol."},{"key":"3097_CR18","doi-asserted-by":"publisher","first-page":"4383","DOI":"10.1158\/0008-5472.CAN-12-3385","volume":"73","author":"H Reuveni","year":"2013","unstructured":"Reuveni, H. et al. Therapeutic destruction of insulin receptor substrates for cancer treatment. Cancer Res. 73, 4383\u20134394 (2013).","journal-title":"Cancer Res."},{"key":"3097_CR19","doi-asserted-by":"publisher","first-page":"1591","DOI":"10.1016\/j.cell.2014.11.020","volume":"159","author":"SA Comerford","year":"2014","unstructured":"Comerford, S. A. et al. Acetate dependence of tumors. Cell 159, 1591\u20131602 (2014).","journal-title":"Cell"},{"key":"3097_CR20","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1038\/s41401-018-0020-z","volume":"40","author":"MZ Gao","year":"2019","unstructured":"Gao, M. Z. et al. Aberrant modulation of ribosomal protein S6 phosphorylation confers acquired resistance to MAPK pathway inhibitors in BRAF-mutant melanoma. Acta Pharmacol. Sin. 40, 268\u2013278 (2019).","journal-title":"Acta Pharmacol. Sin."},{"key":"3097_CR21","doi-asserted-by":"publisher","first-page":"14140","DOI":"10.1074\/jbc.M611563200","volume":"282","author":"L Beuret","year":"2007","unstructured":"Beuret, L. et al. Up-regulation of MET expression by alpha-melanocyte-stimulating hormone and MITF allows hepatocyte growth factor to protect melanocytes and melanoma cells from apoptosis. J. Biol. Chem. 282, 14140\u201314147 (2007).","journal-title":"J. Biol. Chem."},{"key":"3097_CR22","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1158\/2159-8290.CD-12-0095","volume":"2","author":"E Cerami","year":"2012","unstructured":"Cerami, E. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401\u2013404 (2012).","journal-title":"Cancer Discov."},{"key":"3097_CR23","doi-asserted-by":"publisher","first-page":"pl1","DOI":"10.1126\/scisignal.2004088","volume":"6","author":"J Gao","year":"2013","unstructured":"Gao, J. et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1 (2013).","journal-title":"Sci. Signal."},{"key":"3097_CR24","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1038\/s41568-019-0116-x","volume":"19","author":"JJ Havel","year":"2019","unstructured":"Havel, J. J., Chowell, D. & Chan, T. A. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat. Rev. Cancer 19, 133\u2013150 (2019).","journal-title":"Nat. Rev. Cancer"},{"key":"3097_CR25","doi-asserted-by":"publisher","first-page":"1524","DOI":"10.2353\/ajpath.2009.080543","volume":"174","author":"B Horst","year":"2009","unstructured":"Horst, B. et al. Gab2-mediated signaling promotes melanoma metastasis. Am. J. Pathol. 174, 1524\u20131533 (2009).","journal-title":"Am. J. Pathol."},{"key":"3097_CR26","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1002\/ijc.21880","volume":"119","author":"F Meier","year":"2006","unstructured":"Meier, F. et al. The adhesion molecule L1 (CD171) promotes melanoma progression. Int. J. Cancer 119, 549\u2013555 (2006).","journal-title":"Int. J. Cancer"},{"key":"3097_CR27","doi-asserted-by":"publisher","first-page":"3029","DOI":"10.1158\/1078-0432.CCR-08-2768","volume":"15","author":"SA Aziz","year":"2009","unstructured":"Aziz, S. A. et al. Phosphatidylinositol-3-kinase as a therapeutic target in melanoma. Clin. Cancer Res. 15, 3029\u20133036 (2009).","journal-title":"Clin. Cancer Res."},{"key":"3097_CR28","doi-asserted-by":"publisher","first-page":"980","DOI":"10.1038\/sj.jid.5701074","volume":"128","author":"M Karbowniczek","year":"2008","unstructured":"Karbowniczek, M., Spittle, C. S., Morrison, T., Wu, H. & Henske, E. P. mTOR is activated in the majority of malignant melanomas. J. Invest. Dermatol. 128, 980\u2013987 (2008).","journal-title":"J. Invest. Dermatol."},{"key":"3097_CR29","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2017.406","volume":"8","author":"A Azimi","year":"2017","unstructured":"Azimi, A. et al. Silencing FLI or targeting CD13\/ANPEP lead to dephosphorylation of EPHA2, a mediator of BRAF inhibitor resistance, and induce growth arrest or apoptosis in melanoma cells. Cell Death Dis. 8, e3029 (2017).","journal-title":"Cell Death Dis."},{"key":"3097_CR30","doi-asserted-by":"publisher","first-page":"1965","DOI":"10.1158\/1078-0432.CCR-13-3122","volume":"20","author":"H Rizos","year":"2014","unstructured":"Rizos, H. et al. BRAF inhibitor resistance mechanisms in metastatic melanoma: spectrum and clinical impact. Clin. Cancer Res. 20, 1965\u20131977 (2014).","journal-title":"Clin. Cancer Res."},{"key":"3097_CR31","doi-asserted-by":"publisher","first-page":"7095","DOI":"10.2147\/OTT.S182721","volume":"11","author":"S Kakadia","year":"2018","unstructured":"Kakadia, S. et al. Mechanisms of resistance to BRAF and MEK inhibitors and clinical update of US Food and Drug Administration-approved targeted therapy in advanced melanoma. Onco. Targets Ther. 11, 7095\u20137107 (2018).","journal-title":"Onco. Targets Ther."},{"key":"3097_CR32","doi-asserted-by":"publisher","unstructured":"Tian, T., Li, X. & Zhang, J. mTOR signaling in cancer and mTOR inhibitors in solid tumor targeting therapy. Int. J. Mol. Sci. 20, https:\/\/doi.org\/10.3390\/ijms20030755 (2019).","DOI":"10.3390\/ijms20030755"},{"key":"3097_CR33","doi-asserted-by":"publisher","first-page":"688","DOI":"10.1016\/j.trecan.2016.10.006","volume":"2","author":"Y Guri","year":"2016","unstructured":"Guri, Y. & Hall, M. N. mTOR signaling confers resistance to targeted cancer drugs. Trends Cancer 2, 688\u2013697 (2016).","journal-title":"Trends Cancer"},{"key":"3097_CR34","doi-asserted-by":"publisher","first-page":"3947","DOI":"10.18632\/oncotarget.6600","volume":"7","author":"I Penna","year":"2016","unstructured":"Penna, I. et al. Primary cross-resistance to BRAFV600E-, MEK1\/2- and PI3K\/mTOR-specific inhibitors in BRAF-mutant melanoma cells counteracted by dual pathway blockade. Oncotarget 7, 3947\u20133965 (2016).","journal-title":"Oncotarget"},{"key":"3097_CR35","doi-asserted-by":"publisher","first-page":"7037","DOI":"10.1158\/0008-5472.CAN-14-1392","volume":"74","author":"YN Gopal","year":"2014","unstructured":"Gopal, Y. N. et al. Inhibition of mTORC1\/2 overcomes resistance to MAPK pathway inhibitors mediated by PGC1alpha and oxidative phosphorylation in melanoma. Cancer Res. 74, 7037\u20137047 (2014).","journal-title":"Cancer Res."},{"key":"3097_CR36","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.4161\/cbt.29451","volume":"15","author":"D Etnyre","year":"2014","unstructured":"Etnyre, D. et al. Targeting c-Met in melanoma: mechanism of resistance and efficacy of novel combinatorial inhibitor therapy. Cancer Biol. Ther. 15, 1129\u20131141 (2014).","journal-title":"Cancer Biol. Ther."},{"key":"3097_CR37","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1158\/1541-7786.MCR-13-0224-T","volume":"12","author":"JM Silva","year":"2014","unstructured":"Silva, J. M., Bulman, C. & McMahon, M. BRAFV600E cooperates with PI3K signaling, independent of AKT, to regulate melanoma cell proliferation. Mol. Cancer Res. 12, 447\u2013463 (2014).","journal-title":"Mol. Cancer Res."},{"key":"3097_CR38","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1111\/j.1755-148X.2011.00950.x","volume":"25","author":"W Deng","year":"2012","unstructured":"Deng, W. et al. Role and therapeutic potential of PI3K-mTOR signaling in de novo resistance to BRAF inhibition. Pigment Cell Melanoma Res. 25, 248\u2013258 (2012).","journal-title":"Pigment Cell Melanoma Res."},{"key":"3097_CR39","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1111\/pcmr.12259","volume":"27","author":"GR Kardos","year":"2014","unstructured":"Kardos, G. R., Dai, M. S. & Robertson, G. P. Growth inhibitory effects of large subunit ribosomal proteins in melanoma. Pigment Cell Melanoma Res. 27, 801\u2013812 (2014).","journal-title":"Pigment Cell Melanoma Res."},{"key":"3097_CR40","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.isci.2018.06.006","volume":"5","author":"Y Yoneyama","year":"2018","unstructured":"Yoneyama, Y. et al. Serine phosphorylation by mTORC1 promotes IRS-1 degradation through SCFbeta-TRCP E3 ubiquitin ligase. iScience 5, 1\u201318 (2018).","journal-title":"iScience"},{"key":"3097_CR41","doi-asserted-by":"publisher","first-page":"204","DOI":"10.5505\/ejm.2019.82713","volume":"24","author":"G Gorgisen","year":"2019","unstructured":"Gorgisen, G., \u00c7ak\u00fdr, T., ate\u00fe, c, GULACAR, I. M. & Yaren, Z. Overexpression of insulin receptor substrate 1 (IRS1) promotes radioresistance in A172 glioblastoma cell line. Eastern J Med. 24, 204\u2013209 (2019).","journal-title":"Eastern J Med."},{"key":"3097_CR42","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1210\/me.2002-0276","volume":"17","author":"H Sun","year":"2003","unstructured":"Sun, H. et al. Insulin-like growth factor I receptor signaling and nuclear translocation of insulin receptor substrates 1 and 2. Mol. Endocrinol. 17, 472\u2013486 (2003).","journal-title":"Mol. Endocrinol."},{"key":"3097_CR43","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1038\/nature11814","volume":"494","author":"M Das Thakur","year":"2013","unstructured":"Das Thakur, M. et al. Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Nature 494, 251\u2013255 (2013).","journal-title":"Nature"},{"key":"3097_CR44","doi-asserted-by":"publisher","first-page":"618","DOI":"10.1158\/2326-6066.CIR-17-0051","volume":"5","author":"J Park","year":"2017","unstructured":"Park, J. et al. SLC45A2: a melanoma antigen with high tumor selectivity and reduced potential for autoimmune toxicity. Cancer Immunol Res. 5, 618\u2013629 (2017).","journal-title":"Cancer Immunol Res."},{"key":"3097_CR45","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.ejca.2016.02.023","volume":"59","author":"A Roesch","year":"2016","unstructured":"Roesch, A. et al. Phenotypic tumour cell plasticity as a resistance mechanism and therapeutic target in melanoma. Eur. J. Cancer 59, 109\u2013112 (2016).","journal-title":"Eur. J. Cancer"},{"key":"3097_CR46","doi-asserted-by":"publisher","first-page":"8737","DOI":"10.18632\/oncotarget.2372","volume":"5","author":"NF Moore","year":"2014","unstructured":"Moore, N. F. et al. Molecular rationale for the use of PI3K\/AKT\/mTOR pathway inhibitors in combination with crizotinib in ALK-mutated neuroblastoma. Oncotarget 5, 8737\u20138749 (2014).","journal-title":"Oncotarget"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-020-03097-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-020-03097-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-020-03097-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,5]],"date-time":"2022-12-05T15:29:36Z","timestamp":1670254176000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-020-03097-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,20]]},"references-count":46,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2020,10]]}},"alternative-id":["3097"],"URL":"https:\/\/doi.org\/10.1038\/s41419-020-03097-2","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,20]]},"assertion":[{"value":"27 June 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 September 2020","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 September 2020","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 October 2020","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"M.A.D. has been a consultant to Roche\/Genentech, Array, Novartis, BMS, GSK, Sanofi-Aventis, and Vaccinex, and he has been the PI of funded research grants to his institution by Roche\/Genentech, GSK, Sanofi-Aventis, Merck, Myriad, and Oncothyreon. The remaining authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"882"}}