Chemogenetic profiling identifies RAD17 as synthetically lethal with checkpoint kinase inhibition.

TitleChemogenetic profiling identifies RAD17 as synthetically lethal with checkpoint kinase inhibition.
Publication TypeJournal Article
Year of Publication2015
AuthorsShen JPaul, Srivas R, Gross A, Li J, Jaehnig EJ, Sun SMing, Bojorquez-Gomez A, Licon K, Sivaganesh V, Xu JL, Klepper K, Yeerna H, Pekin D, Qiu CPing, van Attikum H, Sobol RW, Ideker T
Date Published2015 Nov 3

Chemical inhibitors of the checkpoint kinases have shown promise in the treatment of cancer, yet their clinical utility may be limited by a lack of molecular biomarkers to identify specific patients most likely to respond to therapy. To this end, we screened 112 known tumor suppressor genes for synthetic lethal interactions with inhibitors of the CHEK1 and CHEK2 checkpoint kinases. We identified eight interactions, including the Replication Factor C (RFC)-related protein RAD17. Clonogenic assays in RAD17 knockdown cell lines identified a substantial shift in sensitivity to checkpoint kinase inhibition (3.5-fold) as compared to RAD17 wild-type. Additional evidence for this interaction was found in a large-scale functional shRNA screen of over 100 genotyped cancer cell lines, in which CHEK1/2 mutant cell lines were unexpectedly sensitive to RAD17 knockdown. This interaction was widely conserved, as we found that RAD17 interacts strongly with checkpoint kinases in the budding yeast Saccharomyces cerevisiae. In the setting of RAD17 knockdown, CHEK1/2 inhibition was found to be synergistic with inhibition of WEE1, another pharmacologically relevant checkpoint kinase. Accumulation of the DNA damage marker γH2AX following chemical inhibition or transient knockdown of CHEK1, CHEK2 or WEE1 was magnified by knockdown of RAD17. Taken together, our data suggest that CHEK1 or WEE1 inhibitors are likely to have greater clinical efficacy in tumors with RAD17 loss-of-function.

PubMed URL
Alternate JournalOncotarget
PubMed ID26437225
PubMed Central IDPMC4742139
Grant ListCA148629 / CA / NCI NIH HHS / United States
ES014811 / ES / NIEHS NIH HHS / United States
GM087798 / GM / NIGMS NIH HHS / United States
P30CA047904 / CA / NCI NIH HHS / United States
R01 ES014811 / ES / NIEHS NIH HHS / United States
Bioinformatics and Systems Biology