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Integration of Bioinformatics Approaches and Experimental Validations to Understand the Role of Notch Signaling in Ovarian Cancer
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NOTCH1 intracellular domain stabilization by MDM2 plays a major role in NSCLC response to platinum

Sara Bernardo1, Lisa Brunet1, Quentin Dominique Thomas1

  • 1Oncogenic Pathways in Lung Cancer. Institut de Recherche en Cancérologie de Montpellier (IRCM), Univ Montpellier, Institut Régional du Cancer de Montpellier (ICM), INSERM, Montpellier, Cedex 5, 34298, France.

EMBO Molecular Medicine
|January 16, 2026
PubMed

Insights

Platinum chemotherapy resistance in non-small cell lung cancer (NSCLC) can be overcome. Targeting MDM2 and Notch Intracellular Domain (NICD) with a γ-secretase inhibitor improves survival in NSCLC models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Non-small cell lung cancer (NSCLC) treatment often involves platinum chemotherapy and immune checkpoint inhibitors.
  • Relapse remains a significant challenge, indicating an unmet medical need in NSCLC management.

Purpose of the Study:

  • To investigate the role of DNA damage inducers and the NOTCH1 pathway in platinum resistance in NSCLC.
  • To identify novel therapeutic strategies to overcome chemotherapy resistance in NSCLC.

Main Methods:

  • Studied the effect of DNA damage inducers on Notch Intracellular Domain (NICD) levels.
  • Investigated the interaction between MDM2 and NICD in platinum-treated cells.
  • Utilized NSCLC patient-derived xenografts to test combination therapy (carboplatin and γ-secretase inhibitor).
  • Correlated MDM2 expression with progression-free survival in NSCLC patients.

Main Results:

  • DNA damage inducers, including platinum compounds, increase NICD levels.
  • MDM2 stabilizes NICD through ubiquitination following platinum treatment.
  • Combination therapy with carboplatin and a γ-secretase inhibitor significantly improved survival and reduced tumor growth in resistant NSCLC xenografts.
  • High MDM2 expression in NSCLC tumors correlated with poor outcomes in patients receiving platinum-based chemotherapy.

Conclusions:

  • MDM2-mediated stabilization of NICD is a key mechanism in platinum resistance in NSCLC.
  • Inhibiting NICD generation with γ-secretase inhibitors offers a promising therapeutic strategy to enhance platinum chemotherapy efficacy.
  • Targeting the MDM2/NICD axis presents a novel treatment opportunity for NSCLC patients who relapse after standard therapy.
Keywords:
MDM2NSCLCNotchPlatinum ChemotherapyResistance

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