Abstract 4458: Chk1 inhibition as a novel therapeutic strategy for treating triple negative breast and ovarian cancers

Abstract

Abstract The serine-threonine kinase Chk1 plays a critical role in cell cycle checkpoints induced in response to genotoxic stress and protecting tumour cells with a defective G1 checkpoint from DNA damage induced by cytotoxic chemotherapeutic drugs. Chk1 inhibitors are currently being pursued in the clinic as a therapeutic strategy to potentiate the anti-tumour efficacy of cytotoxic chemotherapeutic drugs without increasing their systemic toxicity. Several genetic studies have suggested that Chk1 may be critical to ensure accurate DNA replication and division during an unperturbed cell cycle and therefore Chk1 inhibitors, administered as single agents, may be beneficial anti-cancer treatments. Triple-negative breast cancer is characterised by the lack of expression of estrogen and progesterone receptors as well as Her2, along with a gene expression profile and phenotypic characteristics consistent with basal-like breast cancer. Such cancers initially respond well to cytotoxic chemotherapy and PARP inhibitors though the overall prognosis for patients with these tumour types is poor. We therefore hypothesised that triple-negative breast cancer may exhibit sensitivity to single-agent Chk1 inhibition. V158411 is a potent, selective inhibitor of the Chk1 and Chk2 kinases and potently inhibited the proliferation of triple-negative breast (average GI50 0.17µM) compared to ER-positive breast (2.3µM), lung (6.3µM) and colon (2.5µM) cancer cells. In addition, two out of three ovarian cell lines exhibited high sensitivity to growth inhibition by V158411 (SKOV-3 0.06µM and A2780 0.39µM). This sensitivity was independent of p53 mutational status, did not correlate with sensitivity to DNA damaging agents and could not be reversed in ER-positive breast cancer cells with 4-hydroxytamoxifen. Chk1 inhibition reduced triple-negative breast and ovarian cancer cell viability, activated H2AX phosphorylation and induced caspase-3/7 dependent apoptosis at doses that correlated with the anti-proliferative effects. V158411 did not induce a consistent cell cycle arrest or cells to undergo a premature mitosis. V158411 still potentiated the cytotoxicity of cisplatin and gemcitabine in p53 deficient cell lines. In an attempt to understand the sensitivity of certain cancer cell types and identify biomarkers to select sensitive patient populations, tumour cell lysates were profiled for proteins involved in the cell cycle, DNA damage response and apoptosis. Sensitivity to V158411 correlated with increased expression of pChk1(S296) and reduced expression of Mcl-1. This study suggests that triple-negative breast and ovarian cancers rely on Chk1 to complete an unperturbed cell cycle and that inhibiting Chk1 results in increased DNA damage and cell death in these tumour types. V158411, administered as a single agent or in combination with chemotherapy could be a novel, effective strategy in treating these cancer types. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4458. doi:10.1158/1538-7445.AM2011-4458