Status of p53 in human cancer cells does not predict efficacy of CHK1 kinase inhibitors combined with chemotherapeutic agents.
DNA damage checkpoints cause cell cycle arrest, allowing DNA repair before resumption of the cell cycle. These checkpoints can be activated through several signaling pathways. Checkpoint activators include p53, checkpoint kinase 1 (CHK1), checkpoint kinase 2 and/or MAPKAP kinase 2 (MK2). Many cancer cells lack p53 activity and, therefore, depend on alternative checkpoint activators to arrest the cell cycle following DNA damage. Inhibition of these pathways is expected to specifically sensitize these p53-deficient cells to DNA damage caused by chemotherapy. Using isogenic p53-proficient and p53-deficient cancer cell lines, we show that inactivation of CHK1, but not MK2, abrogates cell cycle arrest following chemotherapy, specifically in p53-deficient cells. However, we show that CHK1 is required to maintain genome integrity and cell viability, and that p53-proficient cells are no less sensitive than p53-deficient cells to CHK1 inhibition in the presence of DNA damage. Thus, combining CHK1 inhibition with DNA damage does not lead to preferential killing of p53-deficient over p53-proficient cells, and inhibiting CHK1 does not appear to be a promising approach for potentiation of cancer chemotherapy.
Zenvirt
S
S
Unit of Cellular Signaling, Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel.
Kravchenko-Balasha
N
N
Levitzki
A
A
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D016158:Genes, p53 / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011494:Protein Kinases / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D000099190:MAP-Kinase-Activated Kinase 2
D000071877:Checkpoint Kinase 1; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C000605867:CHEK1 protein, human