title: Targeting of apoptotic pathways by SMAC or BH3 mimetics distinctly sensitizes paclitaxel-resistant triple negative breast cancer cells.
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.
authors.affiliation: Molecular Cell Biology Department, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Effrosini G
authors.initials: EG
authors.lastname: Panayotopoulou
authors.affiliation: Molecular Cell Biology Department, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Anna-Katharina
authors.initials: AK
authors.lastname: Müller
authors.affiliation: Institute of Molecular Medicine and Cell Research (IMMZ), Albert Ludwigs-University, 79104 Freiburg, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Börries
authors.affiliation: Institute of Molecular Medicine and Cell Research (IMMZ), Albert Ludwigs-University, 79104 Freiburg, Germany.
authors.forename: Hauke
authors.initials: H
authors.lastname: Busch
authors.affiliation: Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Guohong
authors.initials: G
authors.lastname: Hu
authors.affiliation: Molecular Cell Biology Department, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Sima
authors.initials: S
authors.lastname: Lev
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D040761:Biomimetic Materials / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D009596:Nitrophenols / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology
chemical_list: C501332:ABT-737; D000814:Aniline Compounds; D051017:Apoptosis Regulatory Proteins; C582180:BV6 peptide; C474007:Bax protein (53-86); D001713:Biphenyl Compounds; C412403:DIABLO protein, human; D004151:Dipeptides; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D009596:Nitrophenols; D009842:Oligopeptides; D010446:Peptide Fragments; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D013449:Sulfonamides; C582429:birinapant; D017239:Paclitaxel; C528561:navitoclax
keywords: SMAC mimetics; high-throughput screen; paclitaxel; resistance; triple negative breast cancer