Abstract
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.
Highlights
Gastric cancer (GC) is a heterogeneous disease and recent effort has been focused on exploring subsets of patients who may potentially benefit from molecularly targeted agents [1]
We have found that MER tyrosine kinase (MerTK) inhibitor treatment resulted in considerable inhibition of cell growth and downstream signaling
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
Summary
Gastric cancer (GC) is a heterogeneous disease and recent effort has been focused on exploring subsets of patients who may potentially benefit from molecularly targeted agents [1]. Despite of tremendous effort in attempting to prove the survival benefit from targeted agents in a “target” population (i.e. MET inhibitor in MET overexpressed gastric cancer patients), many trials have failed to show survival benefit [2]. The survival outcome for metastatic gastric cancer patients is still near one year after diagnosis and exploration of novel targets in “target” population in GC is urgently needed [2]. We recently showed that 8.3% (16 of 192) of GC patients demonstrated strong positive MerTK total protein expression and overall they have poor survival outcome [11]. We showed that MerTK-overexpressing GC cells were profoundly inhibited after MerTK knockdown, suggesting that MerTK can be a potential novel therapeutic target in GC [11]
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