IS IT POSSIBLE TO INDUCE HR-DEFICIENCY IN TUMOR CELLS?

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Although PARP inhibitors represent an exciting potential treatment option for HR-deficient tumors, it should be recognized that this only represents a small proportion of all cancers.  Given that most evaluations of germline BRCA1 and BRCA2 mutations has occurred in patients with strong family histories, it is uncertain what the true frequency is for HR-deficiency in the general population.  One study of 977 ovarian cancer patients in Ontario Canada found an overall BRCA deficiency rate of 13.2% (89).  Given this, it is unlikely that PARP inhibitors will represent a broad treatment option as most tumors will have functional HR repair; therefore, any mechanism which could inhibit HR function in cancer cells represents an intriguing treatment strategy as it would allow for PARP inhibitors to be used in tumors where initially no benefit would be predicted.

Preclinical work by Johnson and colleagues has suggested that inducing HR-deficiency in cancer cells may be possible.  Johnson demonstrated that cyclin-dependent kinase-1 (CDK1) phosphorylates BRCA1 at serine 1189, 1191 and 1497 and this action is necessary for BRCA1 to efficiently form repair foci at sites of DNA damage and induce the necessary checkpoint arrest (17).  This observation suggests that inhibition of CDK1 could induce HR-deficiency by limiting overall BRCA1 activity.  Johnson subsequently demonstrated that the administration of a pharmacologic CDK1 inhibitor could stop the formation of RAD51 foci in HR-proficient tumors in vitro and in vivo, confirming that a CDK1 inhibitor could inactivate HR repair.  As expected from these findings, Johnson confirmed that CDK1-treated tumors demonstrated PARP sensitivity in vitro and in vivo.   Johnson also demonstrated that non-transformed cells are not sensitized to PARP inhibitors when CDK1 is inhibited, suggesting that this combination will be tumor-specific if brought forward for clinical development (90).  Based on this preclinical data, the National Cancer Institute has sponsored a phase I clinical trial evaluating the combination of veliparib with the CDK1 inhibitor SCH727965 in patients with advanced solid tumors which are HR-proficient (NCT01434316).  This trial is in dose escalation and results are not yet available.