Targeting Both Oncogenic Signaling and Dependence Receptor Function is Required to Fully Suppress MET Exon 14 Skipping-Driven tumorigenesis
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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BibTeX
@article{tellier2026targeting,
title = {{Targeting Both Oncogenic Signaling and Dependence Receptor Function is Required to Fully Suppress MET Exon 14 Skipping-Driven tumorigenesis}},
author = {Rémi Tellier and Marie Fernandes and Audrey Vinchent and Sonia Paget and Agathe Laratte and Céline Vuillier and Elisabeth Werkmeister and Céline Villenet and Jean-Pascal Meneboo and Nicolas Elie and Florence Giffard and Anne Chotteau-Lelièvre and Eric Wasielewski and Zoulika Kherrouche and Marie-José Truong and Clotilde Descarpentries and Luca Grumolato and Martin Figeac and Alexis Cortot and Laurent Poulain and Andrea Paradisi and David Tulasne},
journal = {Cancer Research},
year = {2026},
month = sep,
doi = {10.1158/0008-5472.can-26-0195},
url = {https://hal.science/hal-05770051v1},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Targeting Both Oncogenic Signaling and Dependence Receptor Function is Required to Fully Suppress MET Exon 14 Skipping-Driven tumorigenesis
AU - Rémi Tellier
AU - Marie Fernandes
AU - Audrey Vinchent
AU - Sonia Paget
AU - Agathe Laratte
AU - Céline Vuillier
AU - Elisabeth Werkmeister
AU - Céline Villenet
AU - Jean-Pascal Meneboo
AU - Nicolas Elie
AU - Florence Giffard
AU - Anne Chotteau-Lelièvre
AU - Eric Wasielewski
AU - Zoulika Kherrouche
AU - Marie-José Truong
AU - Clotilde Descarpentries
AU - Luca Grumolato
AU - Martin Figeac
AU - Alexis Cortot
AU - Laurent Poulain
AU - Andrea Paradisi
AU - David Tulasne
PY - 2026
DA - 2026/09/08
JO - Cancer Research
DO - 10.1158/0008-5472.can-26-0195
UR - https://hal.science/hal-05770051v1
AB - 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.
SN - 0008-5472
SN - 1538-7445
ER -