MDM2 stabilization of Notch intracellular domain upon DNA damage plays a major role in non-small cell lung carcinoma response to platinum chemotherapy

Abstract

ABSTRACTDespite major advances in lung cancer clinical management, majority of patients suffering non-small cell lung carcinoma (NSCLC) are treated in first line with platinum in combination with immune checkpoint inhibitors. Although platinum compounds normally display an initial therapeutic effect, relapse constitutes a major challenge in the clinical management of NSCLC patients. Therefore, it is fundamental to understand the relapse underlying mechanisms to find new therapeutic opportunities to improve patients’ survival. Here, we found that different DNA damage inducers increase the protein levels of Notch Intracellular Domain (NICD), i.e., the active form of NOTCH1. Mechanistically, we unveiled that upon platinum treatment, there was a concomitant increase of MDM2 together with NICD, and we also observed an MDM2-mediated ubiquitination and stabilization of NICD. Of note, using patient-derived xenografts displaying intrinsic carboplatin resistance, we demonstrated that the combination of carboplatin with MDM2 and NICD inhibitors increased survival and reduced tumor growth compared with carboplatin in monotherapy. Moreover, in patients with NSCLC who received platinum chemotherapy, MDM2 expression level in the tumor was correlated with poor progression-free survival, further validating MDM2 key role in the response to platinum compounds. Our findings open a therapeutic opportunity for NSCLC patients, the main lung cancer subtype of the leading cause of death by cancer worldwide.