Poster Presentation NSW State Cancer Conference 2023

Evaluation of novel therapies targeting the p53 and apoptotic pathways in treatment-resistant estrogen receptor-positive breast cancer   (#154)

Fiona H Zhou 1 2 , Chau Lam Miu 1 3 , Chan Jae Lee 1 3 , Leila Eshraghi 1 2 , Sarah Alexandrou 1 2 , Peta Sommerville 1 , Chuan En (Eric) Lam 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. School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia

Estrogen receptor (ER)-positive breast cancer is the most common type of breast cancer, accounting for 70% of cases. The gold standard treatment for advanced and metastatic ER+ breast cancer involves a combination of endocrine therapy (ET) and CDK4/6 inhibitor (CDK4/6i). However, treatment resistance and tumour progression remain significant unmet clinical challenges. One of the most potent tumour suppressor proteins, p53 is inactivated by mutation in over 50% of all cancers. Although in ER+ breast cancer, Tp53 remains wild-type in 80% of cases, its anti-tumour activity is suppressed by ER signalling and dysregulation of its key negative regulator, MDM2. We have previously reported the effectiveness of MDM2 inhibition in treatment-naïve and ET-resistant breast cancer models [1], but its potential role in dual ET and CDK4/6i resistance has not been demonstrated. Here, we aim to evaluate the efficacy of MDM2 inhibition as a potential novel intervention in the context of ET plus CDK4/6i resistance using our unique treatment-resistant models in vitro and in vivo.

We evaluated the MDM2 inhibitor, CGM097 alone and in combination with ET (fulvestrant) or BH3 mimetics (Mcl-1 inhibitor S63845 and Bcl-2/Bcl-xL inhibitor navitoclax) on Tp53WT ER+ breast cancer cell lines: MCF-7 and MCF-7 resistant to fulvestrant and CDK4/6i (palbociclib) (cFasPalbR) with cell viability and colony forming assays, flow cytometry analysis for apoptosis, senescence, and cell cycle, and western blots. We also evaluated these compounds using PDX models of fulvestrant and palbociclib resistant ER+ breast cancer.

Our results demonstrated that CGM097 reduced the viability of cFasPalbR cells in a dose dependant manner by increasing apoptosis, senescence, and cell cycle arrest. Interestingly, the addition of fulvestrant did not further suppress growth of the dual treatment-resistant cell line and PDX models compared to CGM097 alone. However, the growth inhibitory effect of CGM097 stopped once treatment ended, while the combination of CGM097 and fulvestrant exhibited a more persistent growth inhibition. We hypothesise that the addition of fulvestrant resulted in a more permanent senescent state, which could be targeted for apoptosis using BH3 mimetics. Combining CGM097 with S63845 further enhanced the anti-tumour effects by increasing apoptosis in cFasPalbR cells.

In conclusion, MDM2 inhibition demonstrated potent anti-tumour activity in preclinical models of ET and CDK4/6i-resistant breast cancer, both in vitro and in vivo. The combination with fulvestrant or S63845 appeared to enhance the anti-tumour effects of GCM097. These findings provide valuable insights into potential therapeutic strategies for overcoming treatment resistance in ER+ breast cancer.

  1. 1. Portman, N., et al., MDM2 inhibition in combination with endocrine therapy and CDK4/6 inhibition for the treatment of ER-positive breast cancer. Breast Cancer Res, 2020. 22(1): p. 87.