Chemogenetic profiling identifies RAD17 as synthetically lethal with checkpoint kinase inhibition
| Autor: | Katherine Licon, John Paul Shen, Ana Bojorquez-Gomez, Andrew M. Gross, Chu Ping Qiu, Huwate Yeerna, Jia L. Xu, Rohith Srivas, Haico van Attikum, Robert W. Sobol, Vignesh Sivaganesh, Su Ming Sun, Eric J. Jaehnig, Daniel Pekin, Jianfeng Li, Kristin Klepper, Trey Ideker |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Saccharomyces cerevisiae Proteins
DNA damage Antineoplastic Agents Cell Cycle Proteins Saccharomyces cerevisiae Thiophenes Biomarkers Pharmacological Neoplasms Drug Discovery Medicine Humans Urea checkpoint kinase inhibitor CHEK1 Molecular Targeted Therapy RNA Small Interfering CHEK2 Checkpoint Kinase 2 Gene knockdown RAD17 biology business.industry Kinase Cell Cycle Nuclear Proteins Cell cycle Protein-Tyrosine Kinases DNA-Binding Proteins Wee1 Oncology synthetic lethal Checkpoint Kinase 1 Mutation biology.protein Cancer research biomarker business Protein Kinases Research Paper HeLa Cells |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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