Wnt-driven intestinal tumourigenesis is suppressed by Chk1 deficiency but enhanced by conditional haploinsufficiency.

Chk1 is essential in maintaining genomic stability due to its role in cell cycle regulation. Several recent studies have indicated that the abrogation of checkpoints in tumourigenesis through the inhibition of Chk1 may be of therapeutic value. To further investigate the role of Chk1 in the mouse small intestine and its potential role as a therapy for colorectal cancer, we simultaneously deleted Chk1 and Apc in the mouse small intestine. We found that homozygous loss of Chk1 is not compatible with Wnt-driven proliferation and resulted in the suppression of Wnt-driven tumourigenesis in the mouse small intestine. In contrast, heterozygous loss of Chk1 in a Wnt-driven background resulted in an increase in DNA damage and apoptosis and accelerated both tumour development and progression.

Chk1 deficiency in the mouse small intestine results in p53-independent crypt death and subsequent intestinal compensation.

Chk1 is a serine/threonine protein kinase that is activated by a wide range of DNA-damaging agents to slow the cell cycle during S phase and G2/M. Abrogation of these cell-cycle checkpoints using Chk1 inhibitors results in hypersensitivity to DNA-damaging agents in vitro and may provide a potential therapeutic tool to sensitize tumour cells in vivo. We have generated a Cre-Lox-based mouse model in which Chkl can be inducibly deleted from somatic epithelial cells in the adult mouse small intestine and liver. Loss of Chk1 in the liver is tolerated with no apparent phenotype. In contrast, the loss of Chk1 within the small intestine results in immediate DNA damage and high levels of p53-independent apoptosis leading to crypt death. However, the intestine is able to compensate for this death by undergoing complete re-population with Chk1-proficient cells. These data therefore show that Chk1 deficiency is cell lethal, but the intestine can tolerate such lethality at the organ level.