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Synthetic lethality by targeting the RUVBL1/2-TTT complex in mTORC1-hyperactive cancer cells
Shin, Seung Ho Lee, Ji Su Zhang, Jia-Min Choi, Sungbin Boskovic, Zarko V. Zhao, Ran Song, Mengqiu Wang, Rui Tian, Jie Lee, Mee-Hyun
Shin, Seung Ho
Lee, Ji Su
Zhang, Jia-Min
Choi, Sungbin
Boskovic, Zarko V.
Zhao, Ran
Song, Mengqiu
Wang, Rui
Tian, Jie
Lee, Mee-Hyun
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Abstract
Despite considerable efforts, mTOR inhibitors have produced limited success in the clinic. To define the vulnerabilities of mTORC1-addicted cancer cells and to find previously unknown therapeutic targets, we investigated the mechanism of piperlongumine, a small molecule identified in a chemical library screen to specifically target cancer cells with a hyperactive mTORC1 phenotype. Sensitivity to piperlongumine was dependent on its ability to suppress RUVBL1/2-TTT, a complex involved in chromatin remodeling and DNA repair. Cancer cells with high mTORC1 activity are subjected to higher levels of DNA damage stress via c-Myc and displayed an increased dependency on RUVBL1/2 for survival and counteracting genotoxic stress. Examination of clinical cancer tissues also demonstrated that high mTORC1 activity was accompanied by high RUVBL2 expression. Our findings reveal a previously unknown role for RUVBL1/2 in cell survival, where it acts as a functional chaperone to mitigate stress levels induced in the mTORC1-Myc-DNA damage axis.
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Date
2020-07-31
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American Association for the Advancement of Science
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Shin, S. H., Lee, J. S., Zhang, J. M., Choi, S., Boskovic, Z. V., Zhao, R., Song, M., Wang, R., Tian, J., Lee, M. H., Kim, J. H., Jeong, M., Lee, J. H., Petukhov, M., Lee, S. W., Kim, S. G., Zou, L., & Byun, S. (2020). Synthetic lethality by targeting the RUVBL1/2-TTT complex in mTORC1-hyperactive cancer cells. Science advances, 6(31), eaay9131. https://doi.org/10.1126/sciadv.aay9131