Poster Presentation 35th Lorne Cancer Conference 2023

MDM2 inhibition as a novel therapy to overcome treatment resistance in ER-positive breast cancer (#371)

Fiona H Zhou 1 2 , Chan Jae Lee 1 3 , Sarah Alexandrou 1 2 , Peta Somerville 1 , Nimmy Geetha 1 , Allegra Freelander 1 2 , Denise Attwater 1 , Chuan En (Eric) Lam 1 , Leila Eshraghi 1 2 , C Elizabeth Caldon 1 2 , Neil Portman 1 2 , Elgene Lim 1 2
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. St Vincent’s Clinic School, University of New South Wales, Sydney, NSW, Australia
  3. School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia

Approximately 70% of breast cancer cases express the Estrogen receptor (ER). Combination treatment of endocrine therapy (ET) and CDK4/6 inhibitor is the current standard of care therapy for advanced, metastatic ER+ breast cancer patients. However, treatment resistance is inevitable. Since TP53 remains wildtype in the majority of treatment-resistant ER+ breast cancer and its anti-tumour activity is suppressed by its key negative regulator, MDM2, we hypothesize that MDM2 inhibition is a potential therapeutic strategy in this setting.

Here, we performed cell viability assays, cell cycle, apoptosis, and senescence analysis via flow cytometry, and Western blotting to evaluate the anti-tumour effects of the MDM2 inhibitor, NVP-CGM097 alone and in combination with fulvestrant in TP53WT ER+ breast cancer cell line MCF-7, and its fulvestrant-resistant and palbociclib-resistant derivative (cFasPalbR). We demonstrated that NVP-CGM097 reduced cell viability of cFasPalbR cells in a dose dependent manner by increasing apoptosis and senescence while decreasing cell cycle progression through G1 cell cycle arrest. MDM2 inhibition of cFasPalbR cells for 48 hours resulted in upregulation of p53 and its transcriptional targets including MDM2 and p21; and decreased phosphorylated Rb. Our results suggest that inhibiting the p53-MDM2 interaction in treatment-resistant ER+ breast cancer cells to reactivate p53 function led to growth inhibition through cell cycle arrest, apoptosis, and senescence mechanisms. We further examined efficacy of MDM2 inhibition in a patient-derived xenograft (PDX) model of fulvestrant-resistant and palbociclib-resistant ER+ breast cancer, and demonstrated that MDM2 inhibition with NVP-CGM097 slowed tumour growth by reducing cell proliferation and extended survival time.

We conclude that MDM2 inhibition leads to potent anti-tumour activity and represents a rationadl therapeutic strategy to overcome treatment-resistance in ER+ breast cancer.