Abstract 2963: Pharmacologic Chk2-inhibition promotes increased killing of human colorectal cancer cells and protects from gastrointestinal toxicity following Irinotecan/trail death-receptor agonists (TDRA)

Abstract

Abstract Dose-limiting gastrointestinal toxicity following systemic chemotherapy-based treatment regimen is associated with increased cost and reduced cure-rate. Pharmacologic inhibition of Chk2 has the potential to sensitize cancer cells to cancer therapy while at the same time protect normal tissues from toxicity. Cell death in normal tissues and cells is blocked by inhibition or loss of chk2 in a DNA damage-specific manner whereas tumors cells with check-point aberrations are sensitized to death. We show that inhibiting Chk2-by the use the pharmacologic inhibitors of the Chk2-kinase “Chk2 Inhibitor II” (CI-II) and PV-1019 has the potential to both protect the GI mucosa and improve cell-kill of colorectal cancer cells when Irinotecan is combined with trail death-receptor agonists (TDRA). HCT116-Chk2-/- cells were increasingly sensitive to Irinotecan, TDRA and the combination thereof and PV-1019 had single agent activity towards SW620 cells at 10µM and caused sensitization to Irinotecan at lower doses. Gastrointestinal (GI) toxicity in mice following treatment with the TDRA-antibody MD5-1 in combination with high-dose Irinotecan is completely mediated by chk2 since Chk2-deficient mice are protected and pharmacologic inhibition of Chk2 using CI-II following Irinotecan/TDRA reduced the extent of weight loss and lethality associated with GI-toxicity in the mice. Interestingly, chk2-inhibition only conferred significant protection following Irinotecan/TDRA but not fluorouracil/TDRA, suggesting an Irinotecan-specific protection from GI-toxicity. Concomitant pharmacologic inhibition in conjunction with Irinotecan-based therapy may improve the therapeutic window by reducing GI-toxicity and increasingly promote colorectal cancers cell death. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2963. doi:10.1158/1538-7445.AM2011-2963