PARP-1 Inhibitor Shows Promise for Treating Colorectal Cancer

The PARP-1 (poly(ADP-ribose) polymerase) inhibitor ABT-888 was found to be preferentially toxic to colon cancer cells carrying mutations in both copies of the MRE11 DNA-repair gene.

Approximately 15% of all colorectal cancers (CRCs) demonstrate a type of DNA error called microsatellite instability (MSI), and about 82% of those tumors have MRE11 gene mutations. Investigators at the University of Michigan (Ann Arbor, USA) assessed the mutational status of MRE11 in a panel of 17 CRC cell lines and 46 primary tumors and found a strong correlation with MSI status in both cell lines and tumors. They hypothesized that deficiency in MRE11 may sensitize CRC cells to PARP-1 inhibition based on the concept of synthetic lethality. Synthetic lethality arises when a combination of mutations in two or more genes leads to cell death, whereas a mutation in only one of these genes does not.

The investigators used two experimental approaches; including short hairpin RNA knockdown of MRE11 in the wild type and MSS (microsatellite stable) cell line SW-480 and a second cell-line model transfected with mutant MRE11 to confirm the role of MRE11 in conferring sensitivity to PARP-1 inhibition. They reported in the April 1, 2011, issue of the journal Cancer Research that use of the PARP-1 inhibitor ABT-888 revealed preferential cytotoxicity in those MSI cell lines harboring mutations in MRE11 compared with both wild-type cell lines and MSS cell lines. Both models led to changes in proliferation, in response to ABT-888 at different concentrations, and a drug-response effect was not observed, suggesting a possible contribution of additional genes.

University of Michigan clinicians regularly screen for microsatellite instability in patients at high risk of colorectal cancer. In addition, these markers can be easily detected in tissue samples of patients already diagnosed with colorectal cancer. "This is a potential broader application for PARP inhibitors, beyond breast and ovarian cancer. This is a class of drug that has already shown safety in early clinical trials and now might benefit some colorectal cancer patients as well," said first author Dr. Eduardo Vilar-Sanchez, a fellow in hematology and oncology at the University of Michigan.

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