Poster Presentation 37th Lorne Cancer Conference 2025

MDM2 inhibitor is potent against ER-positive breast cancer in a dual endocrine therapy and CDK4/6 inhibitor-resistant setting (#286)

Fiona H Zhou 1 2 3 , Leila Eshraghi 1 2 , Sarah Alexandrou 1 2 , Chan Jae Lee 1 4 , Nimmy Geetha 1 , Peta Somerville 1 , Aliza Yong 1 , Man Ting Siu 1 , Kristine Fernandez 1 , Chau Lam Miu 1 4 , Denise Attwater 1 , 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. South Australian immunoGENomics Cancer Institute, University of Adelaide, Adelaide, South Australia, Australia
  4. School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia

Estrogen receptor (ER)-positive breast cancer accounts for over 70% of all breast cancer cases. Currently, therapy-resistance and tumour progression are significant unmet clinical challenges. While p53 is a potent tumour suppressor protein, its anti-tumour activity is inhibited by ER-signalling and dysregulation of its key negative regulator, MDM2 in ER-positive breast cancer. A potential place for MDM2 inhibition (MDM2i) in the dual resistance to endocrine therapy (ET) and CDK4/6 inhibition (CDK4/6i) has not been explored. Using preclinical in vitro and in vivo models of dual therapy-resistance, our objective is to evaluate the efficacy of MDM2i as a novel intervention in an emerging setting of pressing clinical need.

The MDM2 inhibitor, NVP-CGM097 was evaluated in vitro models of dual therapy resistant ER-positive breast cancer using flow cytometry analysis for apoptosis, senescence, and cell cycle, RNA sequencing analysis, western blots, IHC and Bcl-2 family pro-survival multiplex immunoassays. We also evaluated NVP-CGM097 in vivo using PDX models of ET and CDK4/6i resistant ER-positive breast cancer.

Our results show MDM2 inhibition reduced viability of the dual therapy-resistant breast cancer cell line, MCF-7_FasPalbR by increasing G1 cell cycle arrest and cellular senescence which correlated with the expression of key differentiated gene signatures. In addition,  MCF-7_FasPalbR cells were more sensitive to MDM2 inhibition compared to the ET and CDK4/6i sensitive MCF-7 cell line. Through RNA sequencing and western blotting, we found that NVP-CGM097 treatment resulted in less  enrichment of up regulated DEG in tumour promoting hallmark gene sets including estrogen response  in MCF-7_FasPalbR cells compared to MCF-7 cells. Interestingly, the data from multiplex immunoassays and western blots of FasPalbR cells indicate while NVP-CGM097 increased pro-apoptotic protein levels of BAX, MDM2i also increased anti-apoptotic protein levels of Bcl-xL and reduced pro-apoptotic protein, BIM, and its interaction with Mcl-1. In two PDX models of combined ET and CDK4/6 inhibitor resistance, we further confirm MDM2i suppressed tumour growth and increased survival percentage by reducing cell proliferation and increasing p21 expression without inducing apoptosis.

In conclusion, we demonstrate here that MDM2 inhibition has potent anti-tumour activity in the setting of ER-positive breast cancers resistant to combined endocrine therapy and CDK4/6 inhibitors.