Furthermore, MERTK and/or its ligands were dramatically upregulated in EGFRMT tumors after treatment with OSI in both xenograft models and patient samples, consistent with induction of autocrine/paracrine MERTK activation. Functionally, OSIR cells were more sensitive to MRX-2843 than parental cells, suggesting acquired dependence on MERTK signaling.

Both GAS6 and EGF stimulated downstream PI3K-AKT and MAPK-ERK signaling in parental cells, but only GAS6 activated these pathways in OSI resistant (OSIR) derivative cell lines. Indeed, treatment with MRX-2843, a first-in-class MERTK kinase inhibitor, re-sensitized GAS6-treated NSCLC cells to OSI.

The MERTK ligand GAS6 promoted downstream oncogenic signaling in EGFR-mutated (EGFRMT) NSCLC cells treated with OSI, suggesting a role for MERTK activation in OSI resistance. Acquired resistance is inevitable in non-small cell lung cancers (NSCLCs) treated with osimertinib (OSI), and the mechanisms are not well defined.