MDM2 inhibition restores p53 function to overcome dual endocrine and CDK4/6 inhibitor resistance in ER+ breast cancer

Background Approximately 70% of breast cancers are estrogen receptor (ER)-positive, with endocrine therapy (ET) forming the treatment backbone. ET plus CDK4/6 inhibitors is standard-of-care for advanced and high-risk early-stage ER+ breast cancer. Despite improved outcomes, resistance and progression remain major challenges. p53 is wild type in most ER+ cancers and is suppressed by its negative regulator MDM2. We previously showed that MDM2 inhibition is effective in ET-resistant ER+ models, however its efficacy in the emerging and urgent setting of dual ET/CDK4/6i resistance remains unexplored. Here, we evaluate MDM2 inhibition in dual-resistant ER + preclinical models. Methods We assessed NVP-CGM097 (a selective MDM2 inhibitor) with or without fulvestrant in dual fulvestrant- and palbociclib-resistant ER+ MCF-7 cells (FasPalbR) and a dual-resistant PDX model using RNAseq, western blotting, immunohistochemistry (IHC), and viability assays. Results NVP-CGM097 activated p53 in dual-resistant cells leading to G 1 arrest and senescence. While NVP-CGM097 treated cells did not show increased apoptosis, both pro-apoptotic and anti-apoptotic proteins and interactions were altered, indicating that there is compensatory signalling to suppress the apoptotic response. NVP-CGM097 was effective as a single agent and the inclusion of fulvestrant yielded no additional benefit . In vivo, NVP-CGM097 suppressed tumour growth, prolonged survival, reduced proliferation, and increased p21, without inducing apoptosis. Conclusions NVP-CGM097 demonstrates single agent efficacy in dual-resistant ER+ breast cancer through G 1 arrest and senescence. It is expected that the majority of patients who progress on ET will receive dual ET/CDK4/6i and that the emergence of resistance to this line of therapy is unfortunately inevitable. These findings support the case for clinical evaluation of MDM2 inhibition in this setting of urgent clinical need.