NOTCH1 intracellular domain stabilization by MDM2 plays a major role in NSCLC response to platinum

Despite major advances in the clinical management of non-small cell lung carcinoma (NSCLC), most patients treated with first-line platinum-based chemotherapy combined with immune checkpoint inhibitors will relapse, which constitutes an unmet medical need. Here, we found that various DNA damage inducers increase the levels of Notch Intracellular Domain (NICD), the active form of NOTCH1. Mechanistically, we revealed that, upon platinum treatment, the expression levels of both MDM2 and NICD were increased and that MDM2 stabilised NICD through ubiquitination. Using NSCLC patient-derived xenografts displaying intrinsic carboplatin resistance, we demonstrated that combining carboplatin with a γ-secretase inhibitor, which hinders NICD generation, significantly improves survival and reduces tumour growth compared with carboplatin monotherapy. Furthermore, in patients with NSCLC who received platinum-based chemotherapy, the level of MDM2 expression in the tumour correlated with poor progression-free survival, which further validates the key role of MDM2 in response to platinum compounds. Our findings present a new therapeutic opportunity for patients with NSCLC, the most common form of lung cancer.

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Publication Details

Journal
EMBO Molecular Medicine
Published
2026-01-16
DOI
https://doi.org/10.1038/s44321-025-00354-9
Primary Topic
Cancer-related Molecular Pathways
Type
article
Field-Weighted Citation Impact
0.00

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article

NOTCH1 intracellular domain stabilization by MDM2 plays a major role in NSCLC response to platinum

Hélène Tourrière, J.L. Pujol, Christophe Frémin, Andrea Pasquier et al.
EMBO Molecular Medicine
Cancer-related Molecular Pathways
article

NOTCH1 intracellular domain stabilization by MDM2 plays a major role in NSCLC response to platinum

Hélène Tourrière, J.L. Pujol, Christophe Frémin, Andrea Pasquier, Anais Giry, Laëtitia K. Linares, Alba Santos, Lisa Héron‐Milhavet, emilie Bousquet-Mur, Sara Bernardo, Antonio Maraver, Marion Goussard, Maicol Mancini, Lisa J. Brunet, Céline Bouclier, Eric Fabbrizio, Laura Papon, Amina-Milissa Maacha, Irene Ferrer, Luis G. Paz-Ares, Alexandre Djiane, María Rodríguez, C. Travert, David Bracquemond, Luis M Montuenga, Xavier Quantin, Quentin Dominique Thomas, Marie Colomb, Sylvia-Fenosoa Rasamizafy
article en

Abstract

Despite major advances in the clinical management of non-small cell lung carcinoma (NSCLC), most patients treated with first-line platinum-based chemotherapy combined with immune checkpoint inhibitors will relapse, which constitutes an unmet medical need. Here, we found that various DNA damage inducers increase the levels of Notch Intracellular Domain (NICD), the active form of NOTCH1. Mechanistically, we revealed that, upon platinum treatment, the expression levels of both MDM2 and NICD were increased and that MDM2 stabilised NICD through ubiquitination. Using NSCLC patient-derived xenografts displaying intrinsic carboplatin resistance, we demonstrated that combining carboplatin with a γ-secretase inhibitor, which hinders NICD generation, significantly improves survival and reduces tumour growth compared with carboplatin monotherapy. Furthermore, in patients with NSCLC who received platinum-based chemotherapy, the level of MDM2 expression in the tumour correlated with poor progression-free survival, which further validates the key role of MDM2 in response to platinum compounds. Our findings present a new therapeutic opportunity for patients with NSCLC, the most common form of lung cancer.

EMBO Molecular MedicineVol. 18(2)
Universidad Complutense de Madrid (ES), Centre National de la Recherche Scientifique (FR), Inserm (FR), Université de Montpellier (FR), Research Institute Hospital 12 de Octubre (ES), Clinical Investigation Center Plurithematic Tours (FR), Navarre Institute of Health Research (ES), Clinica Universidad de Navarra (ES), Institut de Recherche en Cancérologie de Montpellier (FR), Hôpital Arnaud de Villeneuve (FR), Centro de Investigación Biomédica en Red de Cáncer (ES), Universidad de Navarra (ES)
Institut National de la Santé et de la Recherche Médicale, Institut National Du Cancer, Direction Générale de l’offre de Soins
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