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Breast Cancer Research
Published in: Breast Cancer Research 1/2020

01-12-2020 | Breast Cancer | Research article

MDM2 inhibition in combination with endocrine therapy and CDK4/6 inhibition for the treatment of ER-positive breast cancer

Authors: Neil Portman, Heloisa H. Milioli, Sarah Alexandrou, Rhiannon Coulson, Aliza Yong, Kristine J. Fernandez, Kee Ming Chia, Ensar Halilovic, Davendra Segara, Andrew Parker, Sue Haupt, Ygal Haupt, Wayne D. Tilley, Alex Swarbrick, C. Elizabeth Caldon, Elgene Lim

Published in: Breast Cancer Research | Issue 1/2020

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Abstract

Background

Resistance to endocrine therapy is a major clinical challenge in the management of oestrogen receptor (ER)-positive breast cancer. In this setting, p53 is frequently wildtype and its activity may be suppressed via upregulation of its key regulator MDM2. This underlies our rationale to evaluate MDM2 inhibition as a therapeutic strategy in treatment-resistant ER-positive breast cancer.

Methods

We used the MDM2 inhibitor NVP-CGM097 to treat in vitro and in vivo models alone and in combination with fulvestrant or palbociclib. We perform cell viability, cell cycle, apoptosis and senescence assays to evaluate anti-tumour effects in p53 wildtype and p53 mutant ER-positive cell lines (MCF-7, ZR75-1, T-47D) and MCF-7 lines resistant to endocrine therapy and to CDK4/6 inhibition. We further assess the drug effects in patient-derived xenograft (PDX) models of endocrine-sensitive and endocrine-resistant ER-positive breast cancer.

Results

We demonstrate that MDM2 inhibition results in cell cycle arrest and increased apoptosis in p53-wildtype in vitro and in vivo breast cancer models, leading to potent anti-tumour activity. We find that endocrine therapy or CDK4/6 inhibition synergises with MDM2 inhibition but does not further enhance apoptosis. Instead, combination treatments result in profound regulation of cell cycle-related transcriptional programmes, with synergy achieved through increased antagonism of cell cycle progression. Combination therapy pushes cell lines resistant to fulvestrant or palbociclib to become senescent and significantly reduces tumour growth in a fulvestrant-resistant patient-derived xenograft model.

Conclusions

We conclude that MDM2 inhibitors in combination with ER degraders or CDK4/6 inhibitors represent a rational strategy for treating advanced, endocrine-resistant ER-positive breast cancer, operating through synergistic activation of cell cycle co-regulatory programmes.
Appendix
Available only for authorised users
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Metadata
Title
MDM2 inhibition in combination with endocrine therapy and CDK4/6 inhibition for the treatment of ER-positive breast cancer
Authors
Neil Portman
Heloisa H. Milioli
Sarah Alexandrou
Rhiannon Coulson
Aliza Yong
Kristine J. Fernandez
Kee Ming Chia
Ensar Halilovic
Davendra Segara
Andrew Parker
Sue Haupt
Ygal Haupt
Wayne D. Tilley
Alex Swarbrick
C. Elizabeth Caldon
Elgene Lim
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2020
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-020-01318-2

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