Sensitization of colorectal cancer to irinotecan therapy by PARP inhibitor rucaparib

Jan 7, 2019Investigational new drugs

PARP inhibitor rucaparib may increase colorectal cancer sensitivity to irinotecan treatment

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Abstract

Rucaparib combined with irinotecan showed significant synergy in treating colorectal cancer cells.

Four PARP inhibitors and three DNA-damaging agents were screened for their effectiveness in colorectal cancer.
Rucaparib demonstrated the greatest synergy with irinotecan compared to other combinations tested.
In microsatellite stable and unstable colorectal cancer cells, the combination altered cell cycle arrest and apoptosis.
In MSI cells, administering rucaparib before irinotecan increased cytotoxicity more than other strategies.
In vivo studies indicated a significant reduction in tumor volume and increased apoptosis with the rucaparib and irinotecan combination.

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Intended to explore synthetic lethality and develop better combinatorial regimens, we screened colorectal cancer (CRC) cells using poly ADP-ribose (PAR) polymerase (PARP) inhibitors and cytotoxic agents. We studied four PARP inhibitors and three DNA-damaging agents, and their combinations using sulforhodamine B assay. Rucaparib demonstrated the greatest synergy with irinotecan, followed by olaparib and PJ34. Rucaparib and irinotecan was further subjected to detailed examination to determine combination index (CI) and underlying mechanism of action. Effectiveness and sequence dependence of this combination were assessed in microsatellite stable (MSS) and unstable (MSI) CRC and HCT116 isogenic cell lines. The degree of cell cycle arrest and apoptosis was determined by FACS. In vivo studies were performed to confirm efficacy of this combination. PAR levels in MSI and PARP expression in MSI and MSS cell lines were diminished upon combinatorial treatment. HCT116 isogenic cells revealed the importance of p21, p53 and PTEN in exerting synergy. In MSI cells, administration of rucaparib prior to irinotecan enhanced cytotoxicity compared to other strategies explored. FACS revealed S-phase arrest and increased late-stage apoptosis in MSS, and G2-M arrest and total and early-stage apoptosis in MSI cells. In in vivo murine xenograft models, a significant reduction in tumor volume and expression of Ki67, pancytokeratin and RPS6KB1, and increase in expression of caspase 3 were observed with the combination. In conclusion, among the various combinations studied, rucaparib plus irinotecan was the most synergistic one. Alterations in cell cycle arrest and apoptosis were dependent on MSI status in CRC cells.

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Abstract

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