Investigating the Use of Targeted Therapies for Triple‐Negative Breast Cancer

Abstract

Triple‐negative breast cancer (TNBC) accounts for 15‐20% of all diagnosed breast cancers. It is characterized by lack of expression of estrogen receptor and progesterone receptor and an absence of HER2 amplification. TNBC is aggressive, highly metastatic, and resistant to current chemotherapies. TNBC frequently harbors mutations in TP53, suggesting that therapies that exploit this vulnerability may be an effective treatment option. In particular, p53‐deficient cells are hypothesized to be highly sensitive to inhibitors of checkpoint kinase 1 (Chk1) due to checkpoint abrogation. We have evaluated the use of mammosphere cultures as an in vitro system for testing the sensitivity of TNBC tumor cells to chemotherapy and targeted therapy. We hypothesized that mammospheres would display higher levels of chemo‐resistance than adherent cells, due to their ability to enrich for tumor initiating cells (TICs), which have been shown to display chemo‐resistance. However, we reasoned that molecularly targeted therapies should maintain their effect in TICs, since the pathways that are targeted would remain vulnerable. To test these hypotheses, we evaluated the effect of cisplatin (DNA damaging agent, chemotherapy) and LY2606368 (inhibitor of Chk1, targeted therapy) on the viability of TNBC cells. Our data suggest that the TIC population of a tumor may retain its sensitivity to targeted therapy despite resistance to cytotoxic chemotherapy. Further studies are necessary to determine if targeted therapy can impair TIC self‐renewal capacity, to evaluate combination therapies, and to verify these results in vivo.Funding: Komen Foundation; Cancer Prevention & Research Institute of Texas