Oncotarget

Research Papers:

Targeting of apoptotic pathways by SMAC or BH3 mimetics distinctly sensitizes paclitaxel-resistant triple negative breast cancer cells

Effrosini G. Panayotopoulou, Anna-Katharina Müller, Melanie Börries, Hauke Busch, Guohong Hu and Sima Lev _

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Oncotarget. 2017; 8:45088-45104. https://doi.org/10.18632/oncotarget.15125

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Abstract

Effrosini G. Panayotopoulou1, Anna-Katharina Müller1, Melanie Börries2, Hauke Busch2, Guohong Hu3, Sima Lev1

1Molecular Cell Biology Department, Weizmann Institute of Science, Rehovot 76100, Israel

2Institute of Molecular Medicine and Cell Research (IMMZ), Albert Ludwigs-University, 79104 Freiburg, Germany

3Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China

Correspondence to:

Sima Lev, email: [email protected]

Keywords: triple negative breast cancer, paclitaxel, resistance, SMAC mimetics, high-throughput screen

Received: September 13, 2016     Accepted: January 24, 2017     Published: February 06, 2017

ABSTRACT

Standard chemotherapy is the only systemic treatment for triple-negative breast cancer (TNBC), and despite the good initial response, resistance remains a major therapeutic obstacle. Here, we employed a High-Throughput Screen to identify targeted therapies that overcome chemoresistance in TNBC. We applied short-term paclitaxel treatment and screened 320 small-molecule inhibitors of known targets to identify drugs that preferentially and efficiently target paclitaxel-treated TNBC cells. Among these compounds the SMAC mimetics (BV6, Birinapant) and BH3-mimetics (ABT-737/263) were recognized as potent targeted therapy for multiple paclitaxel-residual TNBC cell lines. However, acquired paclitaxel resistance through repeated paclitaxel pulses result in desensitization to BV6, but not to ABT-263, suggesting that short- and long-term paclitaxel resistance are mediated by distinct mechanisms. Gene expression profiling of paclitaxel-residual, -resistant and naïve MDA-MB-231 cells demonstrated that paclitaxel-residual, as opposed to -resistant cells, were characterized by an apoptotic signature, with downregulation of anti-apoptotic genes (BCL2, BIRC5), induction of apoptosis inducers (IL24, PDCD4), and enrichment of TNFα/NF-κB pathway, including upregulation of TNFSF15, coupled with cell-cycle arrest. BIRC5 and FOXM1 downregulation and IL24 induction was also evident in breast cancer patient datasets following taxane treatment. Exposure of naïve or paclitaxel-resistant cells to supernatants of paclitaxel-residual cells sensitized them to BV6, and treatment with TNFα enhanced BV6 potency, suggesting that sensitization to BV6 is mediated, at least partially, by secreted factor(s). Our results suggest that administration of SMAC or BH3 mimetics following short-term paclitaxel treatment could be an effective therapeutic strategy for TNBC, while only BH3-mimetics could effectively overcome long-term paclitaxel resistance.


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