Reference Detail

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