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.

Authors

Suvendu Giri, Boobash Raj Selvadurai, Nitin Gupta, Arturo Simoni-Nieves, Alessandro Genna, Moshit Lindzen, Rishita Chatterjee, Marieke Van Daele, Deepthi Ramesh Kumar, Mirie Zerbib, Roni Oren, Isabelle Sophie Meijer, Elisabeth Franziska Wippich, Yahel Avraham, Rony Dahan, Yuya Haga, Laura E Kilpatrick, Simon Platt, Stephen J Hill, Lipika R Pal, Eytan Ruppin, Yasuo Tsutsumi, Eliane Hadas Yardeni, Muhammad Abu Ahmad, Olga Radinsky, Donatella Romaniello, Mattia Lauriola, Angel Porgador, Yosef Yarden

Published in

Advanced science (Weinheim, Baden-Wurttemberg, Germany). Pages e78290. Oct 14, 2026. Epub Oct 14, 2026.

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.

PMID:
42875888
Bibliographic data and abstract were imported from PubMed on 15 Oct 2026.

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