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In vitro activity of the mTOR inhibitor everolimus, in a large panel of breast cancer cell lines and analysis for predictors of response

  • Preclinical study
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Abstract

Everolimus (RAD001, Afinitor®) is an oral, selective mTOR inhibitor recently approved by the US-FDA in combination with exemestane for treatment of hormone receptor positive advanced breast cancer. To date, no molecular predictors of response to everolimus in breast cancer have been identified. We hypothesized predictive markers could be identified using preclinical models. Using a molecularly characterized panel of human breast cancer and immortalized breast epithelial cell lines, we determined sensitivity to everolimus alone or in combination with ER− or HER2− targeted therapy. Gene expression microarrays and comparative genomic hybridization were performed on the cell lines to identify predictors of response to everolimus. Among 13 everolimus-sensitive cell lines, 10/13(77 %) were luminal, while in 26 resistant cell lines, 16/26(62 %) were non-luminal, and 10/26(38 %) were luminal. Only 3/24 non-luminal lines were sensitive, two of which were HER2+. Everolimus enhanced the anti-proliferative effect of both tamoxifen (TAM) and fulvestrant (FUL) in ER+ breast cancer cell lines, as well as trastuzumab in HER2+ cell lines. Everolimus + FUL but not everolimus + TAM reversed acquired resistance to TAM. Everolimus inhibited mTOR in tested cell lines by decreasing S6 phosphorylation, mediating its anti-proliferative effect by G0/G1 cell cycle arrest and induction of apoptosis. Chromosomal amplifications of AURKA (p value = 0.04) and HER2 (p value = 0.03) were each associated with increased sensitivity to everolimus. Transcript expression microarrays identified GSK3A, PIK3R3, KLF8, and MAPK10 among the genes overexpressed in sensitive luminal lines, while PGP, RPL38, GPT, and GFAP were among the genes overexpressed in resistant luminal cell lines. These preclinical in vitro data provide further support for continued clinical development of everolimus in luminal (ER+ or HER2+) breast cancer in combination with targeted therapies. We identified several potential molecular markers associated with response to everolimus that will require validation in clinical material.

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Abbreviations

ANOVA:

Analysis of variance

EMT:

Epithelial-to-mesenchymal transition

ER:

Estrogen receptor

FITC:

Fluorescein isothiocyanate

FUL:

Fulvestrant

IC50 :

Drug concentration that provides 50 % growth inhibition

mTOR:

Mammalian target of rapamycin

HER2:

Human epidermal growth factor receptor 2

Nim-DAPI:

Nuclear isolation medium–4,6-diamidino-2-phenylindole dihydrochloride

OS:

Overall survival

PI3K:

Phosphoinositide 3-kinase

PFS:

Progression-free survival

PTEN:

Phosphatase and tensin homolog

RR:

Relative risk

TAM:

Tamoxifen

TNBC:

Triple-negative breast cancer

TTP:

Time to progression

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Acknowledgments

DJS received Department of Defense Innovator Award W81XWH-11-1-0104. The work is also funded by a gift to DJS by The Wittich Family Project for Emerging Therapies in Breast Cancer at UCLA’s Jonsson Comprehensive Cancer Center. Dr. Hurvitz receives support from the National Cancer Institute of the National Institutes of Health under Award Number P30CA016042 and from the STOP CANCER Marni Levine Memorial Seed Grant. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Conflict of interest

Sara Hurvitz: travel to international conferences reimbursed by Novartis, Boehringer-Ingelheim, OBI Pharma and Roche, honorarium from Genentech, research funding by Novartis Pharmceuticals, Corp. Dennis J. Slamon: honoraria from Speakers Bureau- Genentech and Sanofi; ownership interest, Amgen; consultant/advisory board, Novartis Pharmaceuticals. Richard Finn: Novartis Pharmaceuticals, Corp research funding. David Chen and Ronald Linnartz: Novartis Pharmaceuticals, Corp. employment and stock ownership. This work was funded in part by Novartis. Other authors have no potential conflict of interest to disclose.

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  1. Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Sara A. Hurvitz, Ondrej Kalous, Dylan Conklin, Amrita J. Desai, Judy Dering, Lee Anderson, Neil A. O’Brien, Teodora Kolarova, Richard S. Finn & Dennis J. Slamon

  2. Novartis Pharmaceuticals, Basel, Switzerland

    Ronald Linnartz & David Chen

  3. University of California, Los Angeles, 2825 Santa Monica Blvd, TORL Suite 209, Santa Monica, CA, 90404, USA

    Sara A. Hurvitz

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  1. Sara A. Hurvitz
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Correspondence to Sara A. Hurvitz.

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Hurvitz, S.A., Kalous, O., Conklin, D. et al. In vitro activity of the mTOR inhibitor everolimus, in a large panel of breast cancer cell lines and analysis for predictors of response. Breast Cancer Res Treat 149, 669–680 (2015). https://doi.org/10.1007/s10549-015-3282-x

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  • DOI: https://doi.org/10.1007/s10549-015-3282-x

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