Investigating the use of Chk1 Inhibitors 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 ~50% of patients do not respond to first line chemotherapy. 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 evaluated the efficacy of two clinically relevant Chk1 inhibitors, LY2606368 (LY) and SCH900776 (SCH), to elucidate the reasons for differing cellular response to the two drugs and evaluate the potential for synergy of each drug in combination with different DNA damaging agents. We hypothesized that both agents would synergize with gemcitabine regardless of p53 status, but would only synergize in combination with cisplatin in p53‐deficient cells. We tested the effects of LY and SCH alone and in combination with cisplatin or gemcitabine on cell viability, cell proliferation, and relevant signaling pathways in a TNBC cell line. Our data suggest that the differential cellular response to the two drugs is mainly due to a difference in potency. LY, but not SCH, preferentially sensitizes p53‐deficient cells to cisplatin. Notably, both LY and SCH synergize with gemcitabine regardless of p53 status, suggesting that Chk1 inhibitors + gemcitabine might be effective in both p53‐proficient and p53‐deficient backgrounds. Further studies are necessary to more fully evaluate the synergistic potential between cisplatin and LY or SCH, to characterize the sensitivity of cells carrying mutant p53, and to verify these results in vivo.Support or Funding InformationKomen Foundation; Cancer Prevention & Research Institute of Texas