Abstract 129: RAD17 loss of function is synthetically lethal with the checkpoint kinase inhibitors AZD7762 or MK-1775
| Autor: | John Paul Shen, Ana Bojorquez-Gomez, Jia L. Xu, Trey Ideker, Andrew M. Gross, Huwate Yeerna, Katherine Licon, Vignesh Sivaganesh, Rohith Srivas, Robert W. Sobol, Jianfeng Li |
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| Rok vydání: | 2015 |
| Předmět: | |
| Zdroj: | Cancer Research. 75:129-129 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Synthetic lethal interactions are a type of genetic interaction in which the simultaneous loss of function of two genes in combination results in cell death. Recently, there has been much interest in the discovery of drugs that are selectively toxic to cancer cells by targeting proteins that form synthetic lethal interactions with tumor specific mutations. He we have identified that RAD17 loss of function is synthetically lethal with AZD7762, an inhibitor of Chk1 and Chk2, and with MK-1775, an inhibitor of Wee1. HeLa or LN428 glioblastoma cells were selectively responsive to AZD7762 or MK-1775 following shRNA-mediated depletion of RAD17. Cells with dual knockdown of CHEK1 and CHEK2 or knockdown of WEE1 were also sensitized to RAD17 knockdown. At baseline, cells with RAD17 knockdown had greater expression of the DNA damage marker H2AX, an effect that was magnified by either chemical inhibition or siRNA-mediated knockdown of CHEK1/2 or WEE1. Accumulation of H2AX was observed primarily in S and G2 phases, RAD17 loss did not have a significant effect on cell cycle progression. The combination of AZD7762 and MK-1775 resulted in synergistic toxicity in RAD17 knockdown but not control cells. Collectively, these results demonstrate that RAD17 loss of function sensitizes cells to inhibition of S and G2/M checkpoint kinases, resulting in greater accumulation of DNA damage and ultimately cell death. We suggest that AZD7762 and MK-1775 may have greater clinical efficacy in tumors with RAD17 mutation or deletion. Citation Format: John Paul Shen, Rohith Srivas, Ana Bojorquez-Gomez, Katherine Licon, Vignesh Sivaganesh, Jia L. Xu, Huwate Yeerna, Andrew Gross, Jian Feng Li, Robert Sobol, Trey Ideker. RAD17 loss of function is synthetically lethal with the checkpoint kinase inhibitors AZD7762 or MK-1775. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 129. doi:10.1158/1538-7445.AM2015-129 |
| Databáze: | OpenAIRE |
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