Fc‐Dependent Targeting of the GAS6–MERTK Axis With Monoclonal and Bispecific Antibodies Overcomes Drug Resistance Across EGFR Mutations in Exons 19, 20, and 21

Abstract

ABSTRACT Resistance of lung cancer to EGFR‐targeting tyrosine kinase inhibitors (TKIs) like osimertinib frequently results from secondary mutations or activation of bypass signaling pathways. Re‐analysis of clinical data unveiled elevated expression of GAS6 and its receptor MERTK in lung cancer patients developing resistance to osimertinib. This implied that the GAS6–MERTK axis could represent a therapeutic vulnerability. Functionally, GAS6 overexpression enhanced cancer cell survival, whereas a new anti‐GAS6 antibody delayed tumor relapses in xenograft models. Similarly, ablation of MERTK sensitized lung cancer cells to osimertinib, revealing a bypass crosstalk between EGFR and MERTK, likely taking place within caveolae. An anti‐MERTK antibody was generated, and a bispecific antibody, Bis‐EM, targeting both EGFR and MERTK, was designed. Bis‐EM promoted the degradation of both receptors and displayed the capacity to promote immune‐mediated cell killing. In combination with TKIs, concurrent antibody‐mediated inhibition of MERTK and EGFR suppressed the growth of TKI‐resistant spheroids. Co‐treatment with Bis‐EM and TKIs delayed tumor relapses in an Fc‐dependent manner across patient‐derived xenografts harboring clinically challenging EGFR exon 20 insertions and other mutations. Collectively, these findings identify the GAS6–MERTK axis as an important driver of drug resistance and provide a strong rationale for the clinical development of Bis‐EM.