MERTK mediates intrinsic and adaptive resistance to AXL-targeting agents.

The TAM (TYRO-3， AXL， MERTK) family receptor tyrosine kinases (RTKs) play an important role in promoting growth， survival， and metastatic spread of several tumor types. AXL and MERTK are overexpressed in head and neck squamous cell carcinoma (HNSCC)， triple-negative breast cancer (TNBC)， and non-small cell lung cancer (NSCLC)， malignancies that are highly metastatic and lethal. AXL is the most well-characterized TAM receptor and mediates resistance to both conventional and targeted cancer therapies. Since AXL is highly expressed in aggressive tumor types， cancer patients are currently being enrolled in clinical trials testing AXL inhibitors. In the current study， we analyzed the effects of AXL inhibition using a small molecule AXL inhibitor， monoclonal antibody therapy， and siRNA in HNSCC， TNBC， and NSCLC preclinical models. Anti-AXL targeting strategies had limited efficacy across these different models which our data suggests could be attributed to upregulation of MERTK. MERTK expression was increased in cell lines and patient-derived xenografts treated with AXL inhibitors and inhibition of MERTK sensitized HNSCC， TNBC， and NSCLC preclinical models to AXL inhibition. Dual targeting of AXL and MERTK led to a more potent blockade of downstream signaling， synergistic inhibition of tumor cell expansion in culture， and reduced tumor growth in vivo. Furthermore， ectopic overexpression of MERTK in AXL inhibitor-sensitive models resulted in resistance to AXL-targeting strategies. These observations suggest that therapeutic strategies co-targeting both AXL and MERTK could be highly beneficial in a variety of tumor types where both receptors are expressed， leading to improved survival for patients with lethal malignancies.