Chk1 inhibition as a novel therapeutic strategy for treating triple-negative breast and ovarian cancers.

Abstract

BACKGROUND:

Chk1 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.

METHODS:

Here 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.

RESULTS:

The 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.

CONCLUSIONS:

This 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.

• Authors: Christopher Bryant, Rebecca Rawlinson, Andrew J Massey
• Journal: BMC cancer (BMC Cancer) Vol. 14 Pg. 570 (Aug 07 2014) ISSN: 1471-2407 [Electronic] England
• PMID: 25104095 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide
• Benzodiazepinones
• Biomarkers, Tumor
• Indoles
• PF 00477736
• Protein Kinase Inhibitors
• Pyrazoles
• Pyridones
• Thiophenes
• V158411
• Deoxycytidine
• Urea
• Protein Kinases
• CHEK1 protein, human
• Checkpoint Kinase 1
• Cisplatin
• Gemcitabine

Topics

• Benzodiazepinones (pharmacology, therapeutic use)
• Biomarkers, Tumor (metabolism)
• Cell Line, Tumor
• Checkpoint Kinase 1
• Cisplatin (pharmacology)
• Deoxycytidine (analogs & derivatives, pharmacology)
• Drug Synergism
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• HT29 Cells
• Humans
• Indoles (pharmacology, therapeutic use)
• MCF-7 Cells
• Ovarian Neoplasms (metabolism, pathology)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Protein Kinases (metabolism)
• Pyrazoles (pharmacology, therapeutic use)
• Pyridones (pharmacology, therapeutic use)
• Thiophenes (pharmacology, therapeutic use)
• Triple Negative Breast Neoplasms (metabolism, pathology)
• Urea (analogs & derivatives, pharmacology, therapeutic use)
• Gemcitabine