Co-targeting MERTK and EGFR with a Bispecific Antibody Overcomes Drug Resistance Across Mutations in Exons 19, 20, and 21

Resistance of lung cancer to EGFR specific tyrosine kinase inhibitors (TKIs), such as osimertinib, often arises from secondary mutations or the activation of bypass signaling pathways. We noted elevated levels of GAS6 and its receptor, MERTK, in patients acquiring resistance to osimertinib, hence hypothesized that the GAS6 MERTK axis can serve as a therapeutic target. GAS6 promoted cell survival and an anti GAS6 antibody we generated delayed tumor relapses in a xenograft model. Likewise, MERTK ablation sensitized lung cancer cells to osimertinib due to a newly described EGFR to MERTK crosstalk. Hence, we developed Bis3, a bispecific antibody targeting both MERTK and EGFR and promoting their degradation. Bis3 plus TKIs cooperatively inhibited the growth of TKI-resistant lung cancer spheroids and markedly delayed relapses of patient-derived xenografts harboring the clinically challenging exon-20 mutations. These findings establish the GAS6 MERTK axis as a driver of drug resistance and provide a rationale for clinical development of Bis3.