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

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.

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Publication Details

Journal
Advanced Science
Published
2026-10-14
DOI
https://doi.org/10.1002/advs.78290
Primary Topic
Lung Cancer Treatments and Mutations
Type
article
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article

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

Roni Oren, Isabelle Meijer, Rony Dahan, Alessandro Genna et al.
Advanced Science
Lung Cancer Treatments and Mutations
article

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

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

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.

Advanced Science
Ben-Gurion University of the Negev (IL), University of Nottingham (GB), Azienda USL di Bologna (IT), National Cancer Institute (US), Weizmann Institute of Science (IL), University of Birmingham (GB), University of Bologna (IT), The University of Osaka (JP)
Openalex Percentile: Top 12%
Lung Cancer Treatments and Mutations
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