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Ref Type Journal Article
PMID (29050198)
Authors Xue G, Kohler R, Tang F, Hynx D, Wang Y, Orso F, Prêtre V, Ritschard R, Hirschmann P, Cron P, Roloff T, Dummer R, Mandalà M, Bichet S, Genoud C, Meyer AG, Muraro MG, Spagnoli GC, Taverna D, Rüegg C, Merghoub T, Massi D, Tang H, Levesque MP, Dirnhofer S, Zippelius A, Hemmings BA, Wicki A
Title mTORC1/autophagy-regulated MerTK in mutant BRAFV600 melanoma with acquired resistance to BRAF inhibition.
Journal Vol Issue Date Pages Journal Short Title
Oncotarget 8 41 2017 Sep 19 69204-69218 Oncotarget
URL
Abstract Text BRAF inhibitors (BRAFi) and the combination therapy of BRAF and MEK inhibitors (MEKi) were recently approved for therapy of metastatic melanomas harbouring the oncogenic BRAFV600 mutation. Although these therapies have shown pronounced therapeutic efficacy, the limited durability of the response indicates an acquired drug resistance that still remains mechanistically poorly understood at the molecular level. We conducted transcriptome gene profiling in BRAFi-treated melanoma cells and identified that Mer tyrosine kinase (MerTK) is specifically upregulated. MerTK overexpression was demonstrated not only in melanomas resistant to BRAFi monotherapy (5 out of 10 samples from melanoma patients) but also in melanoma resistant to BRAFi+MEKi (1 out of 3), although MEKi alone does not affect MerTK. Mechanistically, BRAFi-induced activation of Zeb2 stimulates MerTK in BRAFV600 melanoma through mTORC1-triggered activation of autophagy. Co-targeting MerTK and BRAFV600 significantly reduced tumour burden in xenografted mice, which was pheno-copied by co-inhibition of autophagy and mutant BRAFV600.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
MERTK NCBI c-Eyk|c-mer|MER|RP38|Tyro12 MERTK, MER proto-oncogene, tyrosine kinase, binds ligands, LGALS3, TUB, TULP1 and GAS6, to activate downstream signaling pathways including ERK and AKT (PMID: 29554921) and plays a role in phagocytosis of apoptotic cells (PMID: 28369510). MERTK overexpression has been observed in mantle cell lymphoma (PMID: 29554921), glioblastoma multiforme (PMID: 29553850), gastric cancer (PMID: 29285287), and is associated with resistance to Braf inhibition in Braf mutant melanoma (PMID: 29050198). Unknown
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E MERTK over exp melanoma resistant Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, melanoma cell lines harboring BRAF V600E and overexpression of MERTK were resistant to Zelboraf (vemurafenib) in culture (PMID: 29050198). 29050198