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Ref Type Journal Article
PMID (29285287)
Authors Kim JE, Kim Y, Li G, Kim ST, Kim K, Park SH, Park JO, Park YS, Lim HY, Lee H, Sohn TS, Kim KM, Kang WK, Lee J
Title MerTK inhibition by RXDX-106 in MerTK activated gastric cancer cell lines.
Journal Vol Issue Date Pages Journal Short Title
Oncotarget 8 62 2017 Dec 01 105727-105734 Oncotarget
URL
Abstract Text RXDX-106 is a potent and selective type II pseudo-irreversible (slow off-rate) inhibitor of TYRO3, AXL, MER and c-MET. MER tyrosine kinase (MerTK) is expressed in a variety of malignancies, including gastric cancer (GC). The oncogenic potential of MerTK is supported by various lines of evidence. First, we surveyed 10 GC cell lines for MerTK protein overexpression and MerTk phosphorylation. We next evaluated the change of downstream signaling molecules including (p)-ERK and (p)-AKT, following RXDX-106 treatment. We also investigated the effect of RXDX-106 in patient-derived cell lines to mimic the in vivo condition. The prevalence of MerTK protein overexpression was evaluated in 229 cancer tissue specimens. We have found that MerTK inhibitor treatment resulted in considerable inhibition of cell growth and downstream signaling. In addition, MerTK phosphorylation, not total MerTK expression, is likely more predictive of therapeutic success. p-MerTK protein overexpression by IHC was found in 18% (17/87) of GC patients. Lastly, RXDX-106 inhibited cell proliferation in MerTK activated gastric cancer cell line. These findings provide further evidence of oncogenic roles for MerTK in GC, and demonstrate the importance of kinase activity for MerTK tumorigeneicity and validate RXDX-106, a novel MerTK inhibitor, as a potential therapeutic agent for treatment of GC.

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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
MERTK over exp gastric adenocarcinoma sensitive RXDX-106 Preclinical - Patient cell culture Actionable In a preclinical study, RXDX-106 inhibited proliferation of patient derived gastric cancer cells overexpressing Mertk (PMID: 29285287). 29285287