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NOTCH1 intracellular domain stabilization by MDM2 plays a major role in NSCLC response to platinum
Article de revue   Open Access   Avec comité de lecture

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

Sara Bernardo, Lisa Brunet, Quentin Dominique Thomas, David Bracquemond, Céline Bouclier, Marie Colomb, Maicol Mancini, Eric Fabbrizio, Alba Santos, Sylvia-Fenosoa Rasamizafy, …
EMBO Molecular Medicine
16/01/2026
DOI: https://doi.org/10.1038/s44321-025-00354-9
PMID: 41545766

Résumé

lung cancer dna damage notch pathway carboplatin mdm2
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.

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