title: Modification of tumour cell metabolism modulates sensitivity to Chk1 inhibitor-induced DNA damage.
abstract: Chk1 kinase inhibitors are currently under clinical investigation as potentiators of cytotoxic chemotherapy and demonstrate potent activity in combination with anti-metabolite drugs that increase replication stress through the inhibition of nucleotide or deoxyribonucleotide biosynthesis. Inhibiting other metabolic pathways critical for the supply of building blocks necessary to support DNA replication may lead to increased DNA damage and synergy with an inhibitor of Chk1. A screen of small molecule metabolism modulators identified combinatorial activity between a Chk1 inhibitor and chloroquine or the LDHA/LDHB inhibitor GSK 2837808A. Compounds, such as 2-deoxyglucose or 6-aminonicotinamide, that reduced the fraction of cells undergoing active replication rendered tumour cells more resistant to Chk1 inhibitor-induced DNA damage. Withdrawal of glucose or glutamine induced G1 and G2/M arrest without increasing DNA damage and reduced Chk1 expression and activation through autophosphorylation. This suggests the expression and activation of Chk1 kinase is associated with cells undergoing active DNA replication. Glutamine starvation rendered tumour cells more resistant to Chk1 inhibitor-induced DNA damage and reversal of the glutamine starvation restored the sensitivity of tumour cells to Chk1 inhibitor-induced DNA damage. Chk1 inhibitors may be a potentially useful therapeutic treatment for patients whose tumours contain a high fraction of replicating cells.
authors.affiliation: Vernalis Research, Granta Park, Cambridge, CB21 6GB, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Massey
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000071877:Checkpoint Kinase 1 / Q000378:metabolism*; D002738:Chloroquine / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects*; D004261:DNA Replication; D055808:Drug Discovery; D004734:Energy Metabolism / Q000187:drug effects*; D006801:Humans; D009369:Neoplasms / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D000634:Aminoquinolines; C000612070:GSK2837808A; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D002738:Chloroquine; D000071877:Checkpoint Kinase 1