NOTCH1 intracellular domain stabilization by MDM2 plays a major role in NSCLC response to platinum
Year: 2026
Type: article
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.
Source: EMBO Molecular Medicine
Authors: Sara Bernardo, Lisa Brunet, Quentin Dominique Thomas, David Bracquemond, Céline Bouclier, Marie Colomb, Maicol Mancini, Eric Fabbrizio, Alba Santos, Sylvia-Fenosoa Rasamizafy, Amina-Milissa Maacha, Anais Giry, Emilie Bousquet-Mur, Laura Papon, Marion Goussard, Christophe Fremin, Andrea Pasquier, María Rodríguez, Camille Travert, Jean-Louis Pujol, Laetitia K Linares, Lisa Heron-Milhavet, Alexandre Djiane, Irene Ferrer, Luis Paz-Ares, Xavier Quantin, Luis M Montuenga, Hélène Tourriere, Antonio Maraver
Institutions: Inserm, Institut de Recherche en Cancérologie de Montpellier, Institut Regional du Cancer de Montpellier, Centre National de la Recherche Scientifique, Research Institute Hospital 12 de Octubre, Spanish National Cancer Research Centre, Hospital Universitario 12 De Octubre, Centro de Investigación Biomédica en Red de Cáncer, Centro de Investigación Médica Aplicada, Universidad de Navarra, Clinica Universidad de Navarra, Hôpital Arnaud de Villeneuve, Universidad Complutense de Madrid, Navarre Institute of Health Research
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $7,990
Awards: G1722846474, Exploiting vulnerabilities in EGFR-driven lung adenocarcinoma resistant to osimertinib promoted by MET amplification., Mapping of the inter and intracellular network taking place in the lung cancer tumor microenvironment and its variation in response to carboplatin, Exploring novel connections between oncogenic pathways in lung cancer
OpenAlex ID: W7124430882