title: A potent Chk1 inhibitor is selectively cytotoxic in melanomas with high levels of replicative stress.
abstract: There are few effective treatments for metastatic melanoma. Checkpoint kinase 1 (Chk1) inhibitors are being trialled for their efficacy in enhancing conventional chemotherapeutic agents, but their effectiveness as single agents is not known. We have examined the effectiveness of two novel Chk1 selective inhibitors, AR323 and AR678, in a panel of melanoma cell lines and normal cell types. We demonstrate that these drugs display single-agent activity, with IC50s in the low nanomolar range. The drugs produce cytotoxic effects in cell lines that are most sensitive to these drugs, whereas normal cells are only sensitive to these drugs at the higher concentrations where they have cytostatic activity. The cytotoxic effect is the consequence of inhibition of S-phase Chk1, which drives cells prematurely from late S phase into an aberrant mitosis and results in either failure of cytokinesis or cell death through an apoptotic mechanism. The sensitivity to the Chk1 inhibitors was correlated with the level of endogenous DNA damage indicating replicative stress. Chk1 inhibitors are viable single-agent therapies that target melanoma cells with high levels of endogenous DNA damage. This sensitivity suggests that Chk1 is a critical component of an adaptation to replicative stress in these cells. It also suggests that markers of DNA damage may be useful in identifying the melanomas and potentially other tumour types that are more likely to be sensitive to Chk1 inhibitors as single agents.
authors.affiliation: The University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: K
authors.initials: K
authors.lastname: Brooks
authors.forename: V
authors.initials: V
authors.lastname: Oakes
authors.forename: B
authors.initials: B
authors.lastname: Edwards
authors.forename: M
authors.initials: M
authors.lastname: Ranall
authors.forename: P
authors.initials: P
authors.lastname: Leo
authors.forename: S
authors.initials: S
authors.lastname: Pavey
authors.forename: A
authors.initials: A
authors.lastname: Pinder
authors.forename: H
authors.initials: H
authors.lastname: Beamish
authors.forename: P
authors.initials: P
authors.lastname: Mukhopadhyay
authors.forename: D
authors.initials: D
authors.lastname: Lambie
authors.forename: B
authors.initials: B
authors.lastname: Gabrielli
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000071877:Checkpoint Kinase 1; D004249:DNA Damage / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008545:Melanoma / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D016196:S Phase / Q000187:drug effects; D013312:Stress, Physiological / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1