Abstract
BackgroundChk1 inhibitors are currently in clinical trials as putative potentiators of cytotoxic chemotherapy drugs. Chk1 inhibitors may exhibit single agent anti-tumor activity in cancers with underlying DNA repair, DNA damage response or DNA replication defects.MethodsHere we describe the cellular effects of the pharmacological inhibition of the checkpoint kinase Chk1 by the novel inhibitor V158411 in triple-negative breast cancer and ovarian cancer. Cytotoxicity, the effect on DNA damage response and cell cycle along with the ability to potentiate gemcitabine and cisplatin cytotoxicity in cultured cells was investigated. Western blotting of proteins involved in DNA repair, checkpoint activation, cell cycle and apoptosis was used to identify potential predictive biomarkers of Chk1 inhibitor sensitivity.ResultsThe Chk1 inhibitors V158411, PF-477736 and AZD7762 potently inhibited the proliferation of triple-negative breast cancer cells as well as ovarian cancer cells, and these cell lines were sensitive compared to ER positive breast and other solid cancer cells lines. Inhibition of Chk1 in these sensitive cell lines induced DNA damage and caspase-3/7 dependent apoptosis. Western blot profiling identified pChk1 (S296) as a predictive biomarker of Chk1 inhibitor sensitivity in ovarian and triple-negative breast cancer and pH2AX (S139) in luminal breast cancer.ConclusionsThis finding suggests that Chk1 inhibitors either as single agents or in combination chemotherapy represents a viable therapeutic option for the treatment of triple-negative breast cancer. pChk1 (S296) tumor expression levels could serve as a useful biomarker to stratify patients who might benefit from Chk1 inhibitor therapy.
Highlights
Chk1 inhibitors are currently in clinical trials as putative potentiators of cytotoxic chemotherapy drugs
To test the hypothesis that triple-negative breast cancers are sensitive to Chk1 inhibitors in the absence of cytotoxic chemotherapy agents, a panel of sporadic triple-negative and luminal breast cancer cell lines [31] as well as several ovarian cancer cell lines were tested for their sensitivity to V158411 and compared against a panel of cell lines derived from cancers of the lung, colon or prostate
We confirmed the sensitivity of Triple-negative breast cancer (TNBC) and ovarian cancer cell lines to Chk1 inhibition with two additional Chk1 inhibitors PF-477736 [26] and AZD7762 [27]
Summary
Chk inhibitors are currently in clinical trials as putative potentiators of cytotoxic chemotherapy drugs. Breast cancer is the most common cancer affecting women and the second most common cause of death due to cancer [1]. This highly heterogeneous disease has been classified into various subgroups (namely luminal, HER2 positive, basal-like and normal breast) based on gene expression profiles and phenotypic characteristics [2]. TNBC shares many of the gene expression profiles and phenotypical features of basal-like breast cancer [5,6]. Whilst basal-like and triple-negative breast cancers have been demonstrated to be chemo-sensitive to neoadjuvant therapy, the relapse rates are more aggressive resulting in a worse overall survival [7,8]. Unlike ER, PR or HER2 positive tumors where clear molecular targets for therapeutic intervention exist, identifying specific molecular targets for TNBC has proved more elusive
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