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Decatenation checkpoint‐defective melanomas are dependent on PI 3K for survival
Author(s) -
Brooks Kelly,
Ranall Max,
Spoerri Loredana,
Stevenson Alex,
Gunasingh Gency,
Pavey Sandra,
Meunier Fred,
Gonda Thomas J.,
Gabrielli Brian
Publication year - 2014
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/pcmr.12268
Subject(s) - kinome , g2 m dna damage checkpoint , cell cycle checkpoint , chek1 , microbiology and biotechnology , cancer research , cell culture , cell cycle , biology , spindle checkpoint , kinase , dna damage , apoptosis , chemistry , cell , genetics , cell division , dna , spindle apparatus
Summary 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 si RNA kinome screen to identify kinases responsible and identified PI 3K pathway components. Checkpoint‐defective cell lines were three‐fold more sensitive to small molecule inhibitors of PI 3K. The PI 3K inhibitor PF ‐05212384 promoted apoptosis in the checkpoint‐defective lines, and the increased sensitivity to PI 3K inhibition correlated with increased levels of activated Akt. This work demonstrates that increased PI 3K pathway activation is a necessary adaption for the continued viability of melanomas with a defective decatenation checkpoint.