Targeting Both Oncogenic Signaling and Dependence Receptor Function is Required to Fully Suppress MET Exon 14 Skipping-Driven tumorigenesis

  • Cancer Res. 2026 Sep 8. doi: 10.1158/0008-5472.CAN-26-0195.
Rémi Tellier  1 ,  Marie Fernandes  2 ,  Audrey Vinchent  1 ,  Sonia Paget  1 ,  Agathe Laratte  3 ,  Céline Vuillier  4 ,  Elisabeth Werkmeister  5 ,  Céline Villenet  6 ,  Jean-Pascal Meneboo  3 ,  Nicolas Elie  7 ,  Florence Giffard  8 ,  Anne Chotteau-Lelièvre  3 ,  Eric Wasielewski  9 ,  Zoulika Kherrouche  3 ,  Marie-José Truong  1 ,  Clotilde Descarpentries  9 ,  Luca Grumolato  10 ,  Martin Figeac  3 ,  Alexis B Cortot  11 ,  Laurent Poulain  12 ,  Andrea Paradisi  13 ,  David Tulasne  2
Affiliations
  • 1. CANTHER - Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers France.
  • 2. CANTHER - Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers Lille France.
  • 3. Université de Lille Lille France.
  • 4. Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers France.
  • 5. Center for Infection and Immunity of Lille LILLE France.
  • 6. Université de Lille LILLE, NORD France.
  • 7. Université de Caen Normandie Caen France.
  • 8. Inserm CAEN cedex 5 France.
  • 9. Centre Hospitalier Universitaire de Lille Lille France.
  • 10. Université de Rouen Normandie Mont-Saint-Aignan France.
  • 11. Université de Lille LILLE France.
  • 12. Inserm CAEN France.
  • 13. Centre de Recherche en Cancérologie de Lyon Lyon France.
PMID: 42709847 DOI: 10.1158/0008-5472.CAN-26-0195
Abstract

Receptor Tyrosine Kinases (RTKs) classically function as oncogenic drivers that promote survival and proliferation upon ligand binding. A subset of RTKs can also function as dependence receptors, inducing Apoptosis in the absence of their ligands. Genetic alterations that enhance RTK signaling are well characterized in Cancer and can be targeted with kinase inhibitors, which show limited efficacy in some clinical settings. Elucidation of whether oncogenic mutations can promote tumorigenesis by directly abolishing the pro-apoptotic activity of dependence receptors could help improve strategies to target RTKs. Here, we identified Met exon 14 skipping (METex14Del) as a paradigmatic example of an oncogenic alteration that drives tumorigenesis through genetic inactivation of the dependence receptor function of an RTK. METex14Del removed both the Caspase cleavage site and adjacent CBL-binding motif, preventing generation of the pro-apoptotic p40MET fragment while sustaining oncogenic Met signaling. Uncoupling regulatory functions of Met using genome editing showed that loss of Apoptosis capacity is a critical determinant of METex14Del-driven tumorigenesis. Combined-but not individual-mutation of the Caspase and CBL sites was sufficient to recapitulate resistance to Apoptosis and tumor growth induced by METex14Del in HGF-humanized mouse models. Importantly, inducible re-expression of p40MET in METex14Del-expressing cells restored apoptotic sensitivity, decreased tumor formation in vivo, and resensitized Tumors to capmatinib. Together, these findings redefine RTKs as receptors with dual oncogenic and tumor-suppressive functions and show that disruption of dependence receptor-mediated Apoptosis is an oncogenic mechanism. These results provide a conceptual framework explaining why therapies targeting only RTK signaling may fail and support strategies restoring dependence receptor function to achieve durable tumor suppression.

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