Combination of mTORC1/2 inhibitor vistusertib plus fulvestrant in vitro and in vivo targets oestrogen receptor-positive endocrine-resistant breast cancer

Sunil Pancholi,Sabina C Cosulich,Margaret Hills,Lesley-Ann Martin,Mariana Ferreira Leal,Sophie Chateau-Joubert,Nikiana Simigdala,Eugene Schuster,Elisabetta Maragoni,Ricardo Ribas,Stephen R Johnston,Mitch Dowsett,Lila Zabaglo,Qiong Gao,Andrew Dodson

doi:10.1186/s13058-019-1222-0

Abstract

BackgroundEndocrine therapies are still the main strategy for the treatment of oestrogen receptor-positive (ER+) breast cancers (BC), but resistance remains problematic. Cross-talk between ER and PI3K/AKT/mTORC has been associated with ligand-independent transcription of ER. We have previously reported the anti-proliferative effects of the combination of everolimus (an mTORC1 inhibitor) with endocrine therapy in resistance models, but potential routes of escape via AKT signalling can lead to resistance; therefore, the use of dual mTORC1/2 inhibitors has met with significant interest.MethodsTo address this, we tested the effect of vistusertib, a dual mTORC1 and mTORC2 inhibitor, in a panel of endocrine-resistant and endocrine-sensitive ER+ BC cell lines, with varying PTEN, PIK3CA and ESR1 mutation status. End-points included proliferation, cell signalling, cell cycle and effect on ER-mediated transcription. Two patient-derived xenografts (PDX) modelling endocrine resistance were used to assess the efficacy of vistusertib, fulvestrant or the combination on tumour progression, and biomarker studies were conducted using immunohistochemistry and RNA-seq technologies.ResultsVistusertib caused a dose-dependent decrease in proliferation of all the cell lines tested and reduced abundance of mTORC1, mTORC2 and cell cycle markers, but caused an increase in abundance of EGFR, IGF1R and ERBB3 in a context-dependent manner. ER-mediated transcription showed minimal effect of vistusertib. Combined therapy of vistusertib with fulvestrant showed synergy in two ER+ PDX models of resistance to endocrine therapy and delayed tumour progression after cessation of therapy.ConclusionsThese data support the notion that models of acquired endocrine resistance may have a different sensitivity to mTOR inhibitor/endocrine therapy combinations.

Highlights

Endocrine therapies are still the main strategy for the treatment of oestrogen receptor-positive (ER+) breast cancers (BC), but resistance remains problematic
We explored the relevance of the dual mTORC1/2 inhibitor vistusertib in endocrine-resistant and endocrine-sensitive BC cell lines, as well as in patient-derived xenograft (PDX) models, and showed combination with fulvestrant had superior antiproliferative effects compared with fulvestrant alone
Inhibitory effects of vistusertib on BC cell proliferation We tested the anti-proliferative effect of vistusertib in a panel of isogenic cell lines modelling sensitivity or resistance to endocrine therapy (MCF7, SUM44, HCC1428 and T47D) for which the PIK3CA, PTEN and ESR1 mutation status was previously established [18, 19]

Summary

Introduction

Endocrine therapies are still the main strategy for the treatment of oestrogen receptor-positive (ER+) breast cancers (BC), but resistance remains problematic. Direct targeting of growth factors implicated in resistance has been met with limited success, largely as a result of tumour heterogeneity (reviewed by Johnston et al [2]). Clinical studies have focused on targeting downstream of growth factor signalling, either by direct perturbation of PI3K/mTOR or CDK4/6 within the G1/S checkpoint. De-regulation of the PI3K/AKT/ mTOR pathway has been strongly implicated in resistance to endocrine therapy. AKT has been shown to alter the ER cistrome (genomebinding pattern) effectively changing the ER transcriptional program [3]. These bi-directional interactions between hormonal and kinase signalling pathways potentiate pro-survival signals allowing BC cells to escape endocrine therapy blockade

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