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.
Highlights
Triple negative breast cancer (TNBC) is defined by the absence of estrogen receptor (ER), progesterone receptor (PR) and HER2 amplification and constitutes an exceedingly heterogeneous group of breast cancers, generally stratified into six distinct molecular subtypes including two basal-like subtypes (BL1 and BL2) in addition to immunomodulatory (IM), mesenchymal (M), mesenchymal stem–like (MSL), and luminal androgen receptor (LAR) subtypes [1, 2]
Chemotherapy is the current treatment for most triple-negative breast cancer (TNBC) patients [5], the high frequency of recurrent disease and drug resistance strongly suggests that chemotherapy alone is not sufficient and combination therapy is required
We have chosen paclitaxel as drug of interest, as it is commonly administered in clinical practice to treat TNBC patients [3] and selected the MDAMB-231 cells as a representative line [13], along with six additional TNBC cell lines (SUM159T, BT549, HCC1143, HCC38, HCC1937, MDA-MB-468), which were further characterized throughout the study
Summary
Triple negative breast cancer (TNBC) is defined by the absence of estrogen receptor (ER), progesterone receptor (PR) and HER2 amplification and constitutes an exceedingly heterogeneous group of breast cancers, generally stratified into six distinct molecular subtypes including two basal-like subtypes (BL1 and BL2) in addition to immunomodulatory (IM), mesenchymal (M), mesenchymal stem–like (MSL), and luminal androgen receptor (LAR) subtypes [1, 2]. Among the different chemotherapeutic agents, paclitaxel is commonly used in clinical practice to treat TNBC patients. The taxanes paclitaxel (Taxol) and docetaxel (Taxotere) were the first microtubule-stabilizing agents approved for use in solid tumors [6]. They have demonstrated activity, either as single agents or in combination with other chemotherapeutic or target-specific drugs, against a broad spectrum of malignancies, including breast cancer [7]. The clinical success of taxanes has been compromised by the emergence of drug resistance, as well as numerous side-effects, including neutropenia and neurotoxicity [8]. Drug resistance impedes the initial treatment, as well as the adjuvant setting and has been estimated to cause treatment failure in > 90% of patients with metastatic disease [9]
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