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Peer-reviewedCC BYAdvanced science (Weinheim, Baden-Wurttemberg, Germany)

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.

  • Suvendu Giri1
  • Boobash Raj Selvadurai1
  • Nitin Gupta1
  • Arturo Simoni-Nieves1
  • Alessandro Genna1
  • Moshit Lindzen1
  • Rishita Chatterjee1
  • Marieke Van Daele1
  • Deepthi Ramesh Kumar1
  • Mirie Zerbib2
  • Roni Oren2
  • Isabelle Sophie Meijer1
17 more authors
  • Elisabeth Franziska Wippich1,3
  • Yahel Avraham4
  • Rony Dahan4
  • Yuya Haga5
  • Laura E Kilpatrick6,7
  • Simon Platt6,8
  • Stephen J Hill6,8
  • Lipika R Pal9
  • Eytan Ruppin9
  • Yasuo Tsutsumi5,10,11,12,13
  • Eliane Hadas Yardeni14
  • Muhammad Abu Ahmad15
  • Olga Radinsky15
  • Donatella Romaniello16,17
  • Mattia Lauriola16,17
  • Angel Porgador15
  • Yosef Yarden1
17 affiliations
  1. 1Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel.
  2. 2Department of Veterinary Resources, Weizmann Institute of Science, Rehovot, Israel.
  3. 3Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
  4. 4Department of System Immunology, Weizmann Institute of Science, Rehovot, Israel.
  5. 5Graduate School of Pharmaceutical Sciences, The University of Osaka, Osaka, Japan.
  6. 6Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands, UK.
  7. 7Division of Bimolecular Science and Medicinal Chemistry, School of Pharmacy, Biodiscovery Institute, University of Nottingham, Nottingham, UK.
  8. 8Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham, UK.
  9. 9Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
  10. 10Graduate School of Medicine, The University of Osaka, Osaka, Japan.
  11. 11Institute for Open and Transdisciplinary Research Initiatives, The University of Osaka, Osaka, Japan.
  12. 12Global Center for Medical Engineering and Informatics, The University of Osaka, Osaka, Japan.
  13. 13R3 Institute for Newly-Emerging Science Design, The University of Osaka, Osaka, Japan.
  14. 14Department of Life Science Core Facility, Weizmann Institute of Science, Rehovot, Israel.
  15. 15The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
  16. 16Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy.
  17. 17IRCCS Azienda Ospedaliero-Universitaria di Bologna, University of Bologna, Bologna, Italy.
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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.

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Cite

BibTeXRIS
BibTeX
@article{giri2026fcdependent,
  title = {{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.}},
  author = {Suvendu Giri and Boobash Raj Selvadurai and Nitin Gupta and Arturo Simoni-Nieves and Alessandro Genna and Moshit Lindzen and Rishita Chatterjee and Marieke Van Daele and Deepthi Ramesh Kumar and Mirie Zerbib and Roni Oren and Isabelle Sophie Meijer and Elisabeth Franziska Wippich and Yahel Avraham and Rony Dahan and Yuya Haga and Laura E Kilpatrick and Simon Platt and Stephen J Hill and Lipika R Pal and Eytan Ruppin and Yasuo Tsutsumi and Eliane Hadas Yardeni and Muhammad Abu Ahmad and Olga Radinsky and Donatella Romaniello and Mattia Lauriola and Angel Porgador and Yosef Yarden},
  journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
  year = {2026},
  month = oct,
  doi = {10.1002/advs.78290},
  url = {https://europepmc.org/article/MED/42875888},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - 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.
AU  - Suvendu Giri
AU  - Boobash Raj Selvadurai
AU  - Nitin Gupta
AU  - Arturo Simoni-Nieves
AU  - Alessandro Genna
AU  - Moshit Lindzen
AU  - Rishita Chatterjee
AU  - Marieke Van Daele
AU  - Deepthi Ramesh Kumar
AU  - Mirie Zerbib
AU  - Roni Oren
AU  - Isabelle Sophie Meijer
AU  - Elisabeth Franziska Wippich
AU  - Yahel Avraham
AU  - Rony Dahan
AU  - Yuya Haga
AU  - Laura E Kilpatrick
AU  - Simon Platt
AU  - Stephen J Hill
AU  - Lipika R Pal
AU  - Eytan Ruppin
AU  - Yasuo Tsutsumi
AU  - Eliane Hadas Yardeni
AU  - Muhammad Abu Ahmad
AU  - Olga Radinsky
AU  - Donatella Romaniello
AU  - Mattia Lauriola
AU  - Angel Porgador
AU  - Yosef Yarden
PY  - 2026
DA  - 2026/10/14
JO  - Advanced science (Weinheim, Baden-Wurttemberg, Germany)
DO  - 10.1002/advs.78290
UR  - https://europepmc.org/article/MED/42875888
AB  - 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.
SN  - 2198-3844
ER  -