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

Andrew Sulaiman,Emil Al-Kadi,Xuguang Li,Christina Addison,Jason Chambers,Sarah Mcgarry,Alexandra Phan,Karan Mediratta,Li Li,Jim Dimitroulakos,Lisheng Wang

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 datasets 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 treatment with 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.

Highlights

Breast cancer is one of the leading causes of cancer-related deaths in women throughout the world [1]
For the ALDH+ cancer stem cell (CSC) subpopulation, we found that the combinations of cisplatin+gefitinib, metformin+gefitinib and CMG were all effective (Figure 2E,F,H, Supplemental Figures) with CMG reducing ALDH+ CSCs in both triple-negative breast cancer (TNBC) cell lines by ~90%
Renewed interest in cisplatin has led to more clinical trials, showing efficacious results in the treatment of other types of cancer, including TNBC [41,42,43,44,45]

Summary

Introduction

Breast cancer is one of the leading causes of cancer-related deaths in women throughout the world [1]. The triple-negative breast cancer (TNBC) subtype is characterized as negative for the estrogen receptor 1 (ESR1), progesterone receptor (PGR), and human epidermal growth factor receptor type 2 (HER2). In contrast to other breast cancer subtypes, TNBC does not have specific targets and is reliant on chemotherapeutic regiments for systemic treatment and disproportionately accounts for the majority of breast cancer related deaths. Cisplatin is a platinum 2 complex capable of creating adducts, causing DNA damage, and subsequently inducing apoptosis in a multitude of cancers [2]. Recent clinical trials have showed efficacy of cisplatin in combinational chemotherapy in comparison to conventional chemotherapeutic approaches for the treatment of TNBC [3,4,5]. Others have demonstrated lackluster outcomes, and underlying mechanisms remain convoluted [6,7]

Methods

Results

Conclusion