Synthetic Lethal Interaction between Oncogenic KRAS Dependency and STK33 Suppression in Human Cancer Cells
Synthetic Lethal Interaction between Oncogenic KRAS Dependency and STK33 Suppression in Human Cancer Cells
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DOI：
10.1016/j.cell.2009.03.017
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发表时间：
2009-05-29
期刊：
影响因子：
64.5
通讯作者：
Gilliland, D. Gary
中科院分区：
文献类型：
--
作者：
Scholl, Claudia;Froehling, Stefan;Gilliland, D. Gary
癌基因治疗靶向的另一种选择是对仅在特定致癌突变背景下必不可少的基因进行“合成致死”筛选。我们使用高通量RNA干扰（RNAi）来鉴定携带突变KRAS（最常见的突变人类癌基因）的癌细胞中的合成致死相互作用。我们发现，依赖于突变KRAS的细胞表现出对丝氨酸/苏氨酸激酶STK 33抑制的敏感性，而不依赖于KRAS的细胞不需要STK 33。STK 33以激酶活性依赖性的方式促进癌细胞活力，其通过在突变型KRAS依赖性细胞中选择性地调节由S6 K1诱导的死亡激动剂BAD失活介导的线粒体凋亡的抑制来实现。这些观察结果将STK 33鉴定为突变KRAS驱动的癌症的治疗靶点，并证明了RNAi筛选发现致癌突变产生的功能依赖性的潜力，这些功能依赖性可以对具有“不可破坏的”遗传改变的癌症进行治疗干预。
An alternative to therapeutic targeting of oncogenes is to perform "synthetic lethality'' screens for genes that are essential only in the context of specific cancer-causing mutations. We used high-throughput RNA interference (RNAi) to identify synthetic lethal interactions in cancer cells harboring mutant KRAS, the most commonly mutated human oncogene. We find that cells that are dependent on mutant KRAS exhibit sensitivity to suppression of the serine/threonine kinase STK33 irrespective of tissue origin, whereas STK33 is not required by KRAS-independent cells. STK33 promotes cancer cell viability in a kinase activity-dependent manner by regulating the suppression of mitochondrial apoptosis mediated through S6K1-induced inactivation of the death agonist BAD selectively in mutant KRAS-dependent cells. These observations identify STK33 as a target for treatment of mutant KRAS-driven cancers and demonstrate the potential of RNAi screens for discovering functional dependencies created by oncogenic mutations that may enable therapeutic intervention for cancers with "undruggable'' genetic alterations.