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

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

doi:10.1186/s13058-020-01318-2

Abstract

BackgroundResistance 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.MethodsWe 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.ResultsWe 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.ConclusionsWe 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.

Highlights

Resistance to endocrine therapy is a major clinical challenge in the management of oestrogen receptor (ER)-positive breast cancer
We demonstrate that in endocrine- and cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor-resistant in vitro models, MDM2 inhibition is potentiated by combination with endocrine therapy or CDK4/6 inhibition and that this occurs via an increase in senescence compared to MDM2 inhibition alone
The incidence of TP53 aberration in advanced Oestrogen Receptor (ER)-positive breast cancers was ~ 20%, equivalent to that observed in primary tumours and relatively low compared to other cancer types (International Agency for Research on Cancer, IARC) database

Summary

Introduction

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. 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. Resistant disease that retains ER positivity is typically managed by treating with additional lines of endocrine therapy. The addition of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors to endocrine therapy has become the new standard of care for first- and second-line treatment for advanced breast cancer [3]. Even with the addition of CDK4/6 inhibitors, resistance develops on average within 2–3 years and the need to identify novel targets and therapies in the resistant setting remains pressing [3, 4]

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