Drug Target for Cancer: ChK1

Drug Targets for Cancer: ChK1 and Cancer

Cancer-associated defects of Chk1 are extremely rare, and so far seem limited to cancers of the colon, stomach, and endometrium. Frameshift mutations due to insertion or deletion of single adenine in the polyadenine tract of the Chk1 gene have been reported in colon and endometrial carcinomas with microsatelite instability. The resulting truncated Chk1 proteins are predicted to be defective due to the lack of the C-terminal end of the catalytic domain and the complete loss of the SQ-rich regulatory domain, yet given their heterozygous state, the overall functional impact of these mutations in cancer cells remains uncertain. A shorter isoform of Chk1 mRNA, predicted to encode a protein which lacks a conserved subdomain in the catalytic domain of Chk1, has been detected in a subset of small cell lung cancers. The deleted part of the catalytic domain is predicted to be involved in substrate selectivity, and the significance of the predominant expression of this alternative Chk1 isoform in fetal lung and in small cell cancers, but not in normal adult lung tissue or other types of lung cancers, remains to be established. Despite the fact that Chk1 function and its analogy with Chk2 fit a candidate tumor suppressor gene, the complete deficiency of Chk1 in mice results in early embryonic lethality, and it is yet to be seen whether noncancerous somatic cells lacking Chk1 are viable. On the other hand, deletion of Chk1 in a p53- deficient chicken tumor cell line is tolerable, as are the heterozygous truncation mutations of Chk1 in some human tumors. Thus, it is plausible that either hypomorphic mutations of Chk1 or Chk1 defects that occur during progression of cancer at the stage when cancer cells are less prone to apoptosis (such as those with mutant p53) may contribute to enhanced genetic instability in some cancers. Chemotherapy and radiotherapy kill proliferating cancer cells through generating massive DNA lesions. In the meantime, they activate the Chk1-dependent DDR and cell cycle checkpoints to facilitate cell survival. A conventional idea is that when Chk1 is inhibited, cancer cells lose their ability to respond to and repair DNA damage, enhancing the cell killing effect of chemotherapy or radiotherapy. Therefore, combining Chk1 inhibition with chemotherapy or radiotherapy provides the so-called 'synthetic lethality' effect in cancer.

Drug Targets for Cancer: ChK1 related Products

Other vital drug targets for cancer like ChK1

Drug Targets for Cancer: ChK1 Related Reference

Zhang Y, Hunter T. Roles of Chk1 in cell biology and cancer therapy[J]. International journal of cancer, 2014, 134(5): 1013-1023.
Bartek J, Lukas J. Chk1 and Chk2 kinases in checkpoint control and cancer[J]. Cancer cell, 2003, 3(5): 421-429.

Drug Targets for Cancer: ChK1 Related Information