Development of targeted therapies for triple-negative breast cancer (TNBC) is an unmet\nmedical need. Cisplatin has demonstrated its promising potential for the treatment of TNBC in clinical\ntrials; however, cisplatin treatment is associated with hypoxia that, in turn, promotes cancer stem cell\n(CSC) enrichment and drug resistance. Therapeutic approaches to attenuate this may lead to increased\ncisplatin effcacy in the clinic for the treatment of TNBC. In this report we analyzed clinical datasets of\nTNBC and found that TNBC patients possessed higher levels of EGFR and hypoxia gene expression.\nA similar expression pattern was also observed in cisplatin-resistant ovarian cancer cells. We, thus,\ndeveloped a new therapeutic approach to inhibit EGFR and hypoxia by combination treatment with\nmetformin and gefitinib that sensitized TNBC cells to cisplatin and led to the inhibition of both\nCD44+/CD24 and ALDH+ CSCs. We demonstrated a similar inhibition effcacy on organotypic\ncultures of TNBC patient samples ex vivo. Since these drugs have already been used frequently in\nthe clinic; this study illustrates a novel, clinically translatable therapeutic approach to treat patients\nwith TNBC.
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