Synthetic lethal interactions for the development of cancer therapeutics: biological and methodological advancements |
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Authors: | Shinji Mizuarai Hidehito Kotani |
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Institution: | (1) Department of Oncology, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba Ibaraki, 300-2611, Japan;(2) President’s Office and Business Development, Banyu Pharmaceutical Co., Ltd., Kitanomaru Square, 1-13-12 Kudan-kita, Chiyoda-Ku Tokyo, 102-8667, Japan; |
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Abstract: | Synthetic lethal interaction is defined as a combination of two mutations that is lethal when present in the same cell; each
individual mutation is non-lethal. Synthetic lethal interactions attract attention in cancer research fields since the discovery
of synthetic lethal genes with either oncogenes or tumor suppressor genes (TSGs) provides novel cancer therapeutic targets.
Due to the selective lethal effect on cancer cells harboring specific genetic alterations, it is expected that targeting synthetic
lethal genes would provide wider therapeutic windows compared with cytotoxic chemotherapeutics. Here, we review the current
status of the application of synthetic lethal screening in cancer research fields from biological and methodological viewpoints.
Very recent studies seeking to identify synthetic lethal genes with K-RAS and p53, which are known to be the most frequently
occurring oncogenes and TSGs, respectively, are introduced. Among the accumulating amount of research on synthetic lethal
interactions, the synthetic lethality between BRCA1/2 and PARP1 inhibition has been clinically proven. Thus, both preclinical
and clinical data showing a preferential anti-tumor effect on BRCA1/2 deficient tumors by a PARP1 inhibitor are the best examples
of the synthetic lethal approach of cancer therapeutics. Finally, methodological progress regarding synthetic lethal screening,
including barcode shRNA screening and in vivo synthetic lethal screening, is described. Given the fact that an increasing
number of synthetic lethal genes for major cancerous genes have been validated in preclinical studies, this intriguing approach
awaits clinical verification of preferential benefits for cancer patients with specific genetic alterations as a clear predictive
factor for tumor response. |
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