Preprint Article Version 1 This version is not peer-reviewed

Targeting Hypoxia Sensitizes TNBC to Cisplatin and Promotes Inhibition of Both Bulk and Cancer Stem Cells

Version 1 : Received: 21 July 2020 / Approved: 22 July 2020 / Online: 22 July 2020 (11:32:30 CEST)

A peer-reviewed article of this Preprint also exists.

Sulaiman, A.; McGarry, S.; Chambers, J.; Al-Kadi, E.; Phan, A.; Li, L.; Mediratta, K.; Dimitroulakos, J.; Addison, C.; Li, X.; Wang, L. Targeting Hypoxia Sensitizes TNBC to Cisplatin and Promotes Inhibition of Both Bulk and Cancer Stem Cells. Int. J. Mol. Sci. 2020, 21, 5788. Sulaiman, A.; McGarry, S.; Chambers, J.; Al-Kadi, E.; Phan, A.; Li, L.; Mediratta, K.; Dimitroulakos, J.; Addison, C.; Li, X.; Wang, L. Targeting Hypoxia Sensitizes TNBC to Cisplatin and Promotes Inhibition of Both Bulk and Cancer Stem Cells. Int. J. Mol. Sci. 2020, 21, 5788.

Journal reference: Int. J. Mol. Sci. 2020, 21, 5788
DOI: 10.3390/ijms21165788

Abstract

Development of targeted therapies for triple-negative breast cancer (TNBC) is an unmet medical need. Cisplatin has demonstrated its promising potential for the treatment of TNBC in clinical trials; however, cisplatin treatment is associated with hypoxia that in turn promotes cancer stem cell (CSC) enrichment and drug resistance. Therapeutic approaches to attenuate this may lead to increased cisplatin efficacy in the clinic for the treatment of TNBC. In this report, we analyzed clinical dataset of TNBC and found that TNBC patients possessed higher levels of EGFR and hypoxia gene expression. A similar expression pattern was also observed in cisplatin-resistant ovarian cancer cells. We thus developed a new therapeutic approach to inhibit EGFR and hypoxia by combination of metformin and gefitinib that sensitized TNBC cells to cisplatin and led to the inhibition of both CD44+/CD24- and ALDH+ CSCs. We demonstrated a similar inhibition efficacy on organotypic cultures of TNBC patient samples ex vivo. Since these drugs have already been used frequently in the clinic, this study illustrates a novel, clinically translatable therapeutic approach to treat patients with TNBC.

Subject Areas

Triple Negative Breast Cancer; Cancer Stem Cell; Hypoxia; EGFR; Cisplatin; PDX

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