title: Treatment with the PARP inhibitor, niraparib, sensitizes colorectal cancer cell lines to irinotecan regardless of MSI/MSS status.
abstract: BACKGROUND
  Cells with homologous recombination (HR) deficiency, most notably caused by mutations in the BRCA1 or BRCA2 genes, are sensitive to PARP inhibition. Microsatellite instability (MSI) accounts for 10-15% of colorectal cancer (CRC) and is hypothesized to lead to HR defects due to altered expression of Mre11, a protein required for double strand break (DSB) repair. Indeed, others have reported that PARP inhibition is efficacious in MSI CRC.
  
  
  METHODS
  Here we examine the response to niraparib, a potent PARP-1/PARP-2 inhibitor currently under clinical evaluation, in MSI versus microsatellite stable (MSS) CRC cell lines in vitro and in vivo. We compiled a large panel of MSI and MSS CRC cell lines and evaluated the anti-proliferative activity of niraparib. In addition to testing single agent cytotoxic activity of niraparib, we also tested irinotecan (or SN-38, the active metabolite of irinotecan) activity alone and in combination with niraparib in vitro and in vivo.
  
  
  RESULTS
  In contrast to earlier reports, MSI CRC cell lines were not more sensitive to niraparib than MSS CRC cell lines¸ suggesting that the MSI phenotype does not sensitize CRC cell lines to PARP inhibition. Moreover, even the most sensitive MSI cell lines had niraparib EC50s greater than 10 fold higher than BRCA-deficient cell lines. However, MSI lines were more sensitive to SN-38 than MSS lines, consistent with previous findings. We have also demonstrated that combination of niraparib and irinotecan was more efficacious than either agent alone in both MSI and MSS cell lines both in vitro and in vivo, and that niraparib potentiates the effect of irinotecan regardless of MSI status.
  
  
  CONCLUSIONS
  Our results support the clinical evaluation of this combination in all CRC patients, regardless of MSI status.
authors: Department of Oncology, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115 USA.
authors: Sybil M
authors: SM
authors: Genther Williams
authors: Department of In Vivo Pharmacology, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115 USA.
authors: Apryle M
authors: AM
authors: Kuznicki
authors: Department of In Vivo Pharmacology, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115 USA.
authors: Paula
authors: P
authors: Andrade
authors: Department of Oncology, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115 USA.
authors: Brian M
authors: BM
authors: Dolinski
authors: Department of Oncology, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115 USA ; Current address: Bayer HealthCare, 100 Bayer Road, Whippany, NJ 07891 USA.
authors: Cem
authors: C
authors: Elbi
authors: Department of Oncology, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115 USA.
authors: Ronan C
authors: RC
authors: O'Hagan
authors: Department of Oncology, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115 USA ; Current address: Institute for Applied Cancer Science, 1901 East Road, Unit 1956, Room 4SCR6.1009, Houston, TX 77005 USA.
authors: Carlo
authors: C
authors: Toniatti