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

## TL;DR

This study shows that MDM2 stabilizes NOTCH1 in lung cancer, reducing platinum chemotherapy effectiveness, and suggests targeting NOTCH1 could improve treatment outcomes.

## Contribution

The study identifies MDM2-mediated stabilization of NOTCH1 intracellular domain as a novel mechanism of platinum resistance in NSCLC.

## Key findings

- MDM2 stabilizes NICD through ubiquitination, reducing platinum therapy effectiveness in NSCLC.
- Blocking NICD generation improves survival and tumor growth in platinum-resistant NSCLC xenografts.
- Higher MDM2 expression in NSCLC tumors correlates with worse progression-free survival after platinum therapy.

## 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.

Most patients with NSCLC undergo platinum-based chemotherapy at some point during their treatment. Some patients never respond, and the majority of those who initially respond will eventually relapse, highlighting the need to understand the mechanisms of platinum resistance.

Carboplatin-induced DNA damage increases NOTCH1 intracellular domain (NICD) expression levels.Upon DNA damage, ATM activates MDM2, which then ubiquitinates NICD and stabilises it. This unveils an ATM-MDM2-NICD axis that decreases the effectiveness of platinum therapy.Abolishing NICD generation in vivo makes NSCLC patient-derived xenografts displaying intrinsic resistance to carboplatin more susceptible to platinum-based chemotherapy.Patients with NSCLC who express higher levels of MDM2 have shorter progression-free survival after platinum therapy.

Carboplatin-induced DNA damage increases NOTCH1 intracellular domain (NICD) expression levels.

Upon DNA damage, ATM activates MDM2, which then ubiquitinates NICD and stabilises it. This unveils an ATM-MDM2-NICD axis that decreases the effectiveness of platinum therapy.

Abolishing NICD generation in vivo makes NSCLC patient-derived xenografts displaying intrinsic resistance to carboplatin more susceptible to platinum-based chemotherapy.

Patients with NSCLC who express higher levels of MDM2 have shorter progression-free survival after platinum therapy.

Most patients with NSCLC undergo platinum-based chemotherapy at some point during their treatment. Some patients never respond, and the majority of those who initially respond will eventually relapse, highlighting the need to understand the mechanisms of platinum resistance.