title: Decatenation checkpoint-defective melanomas are dependent on PI3K for survival.
abstract: Melanoma cell lines are commonly defective for the G2-phase cell cycle checkpoint that responds to incomplete catenation of the replicated chromosomes. Here, we demonstrate that melanomas defective for this checkpoint response are less sensitive to genotoxic stress, suggesting that the defective cell lines compensated for the checkpoint loss by increasing their ability to cope with DNA damage. We performed an siRNA kinome screen to identify kinases responsible and identified PI3K pathway components. Checkpoint-defective cell lines were three-fold more sensitive to small molecule inhibitors of PI3K. The PI3K inhibitor PF-05212384 promoted apoptosis in the checkpoint-defective lines, and the increased sensitivity to PI3K inhibition correlated with increased levels of activated Akt. This work demonstrates that increased PI3K pathway activation is a necessary adaption for the continued viability of melanomas with a defective decatenation checkpoint.
authors.affiliation: Translational Research Institute, The University of Queensland Diamantina Institute, Brisbane, Qld, Australia.
authors.forename: Kelly
authors.initials: K
authors.lastname: Brooks
authors.forename: Max
authors.initials: M
authors.lastname: Ranall
authors.forename: Loredana
authors.initials: L
authors.lastname: Spoerri
authors.forename: Alex
authors.initials: A
authors.lastname: Stevenson
authors.forename: Gency
authors.initials: G
authors.lastname: Gunasingh
authors.forename: Sandra
authors.initials: S
authors.lastname: Pavey
authors.forename: Fred
authors.initials: F
authors.lastname: Meunier
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Gonda
authors.forename: Brian
authors.initials: B
authors.lastname: Gabrielli
mesh_terms: D017209:Apoptosis; D059447:Cell Cycle Checkpoints; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002469:Cell Separation; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D005434:Flow Cytometry; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*; D009025:Morpholines / Q000737:chemistry; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells; D014227:Triazines / Q000737:chemistry
chemical_list: D018797:Cell Cycle Proteins; D004250:DNA Topoisomerases, Type II; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering; D014227:Triazines; C549060:gedatolisib
keywords: PI3K; decatenation checkpoint; melanoma; synthetic lethality