Treatment of
non-small cell lung cancer (NSCLC) has been transformed by targeted
therapies directed against molecular aberrations specifically activated within an individual patient's
tumor. However, such
therapies are currently only available against a small number of such aberrations, and new targets and
therapeutics are needed. Our laboratory has previously identified the
MERTK receptor tyrosine kinase (RTK) as a potential drug target in multiple
cancer types, including NSCLC. We have recently developed UNC2025--the first-in-class small molecule inhibitor targeting
MERTK with pharmacokinetic properties sufficient for clinical translation. Here, we utilize this compound to further validate the important emerging biologic functions of
MERTK in
lung cancer pathogenesis, to establish that
MERTK can be effectively targeted by a clinically translatable agent, and to demonstrate that inhibition of
MERTK is a valid treatment strategy in a wide variety of NSCLC lines independent of their driver oncogene status, including in lines with an EGFR mutation, a KRAS/NRAS mutation, an RTK fusion, or another or unknown driver oncogene. Biochemically, we report the selectivity of
UNC2025 for
MERTK, and its inhibition of oncogenic downstream signaling. Functionally, we demonstrate that
UNC2025 induces apoptosis of
MERTK-dependent NSCLC cell lines, while decreasing colony formation in vitro and
tumor xenograft growth in vivo in murine models. These findings provide further evidence for the importance of
MERTK in NSCLC, and demonstrate that
MERTK inhibition by
UNC2025 is a feasible, clinically relevant treatment strategy in a wide variety of NSCLC subtypes, which warrants further investigation in clinical trials.