Scholl Claudia, Fröhling Stefan, Dunn Ian F, Schinzel Anna C, Barbie David A, Kim So Young, Silver Serena J, Tamayo Pablo, Wadlow Raymond C, Ramaswamy Sridhar, Döhner Konstanze, Bullinger Lars, Sandy Peter, Boehm Jesse S, Root David E, Jacks Tyler, Hahn William C, Gilliland D Gary
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Cell. 2009 May 29;137(5):821-34. doi: 10.1016/j.cell.2009.03.017.
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.
除了针对癌基因进行治疗性靶向之外，另一种方法是针对仅在特定致癌突变背景下才必需的基因进行“合成致死”筛选。我们利用高通量RNA干扰（RNAi）来鉴定携带突变型KRAS（最常见的人类致癌基因）的癌细胞中的合成致死相互作用。我们发现，依赖突变型KRAS的细胞对丝氨酸/苏氨酸激酶STK33的抑制表现出敏感性，而与组织来源无关，而不依赖KRAS的细胞则不需要STK33。STK33通过在依赖突变型KRAS的细胞中选择性调节由S6K1诱导的死亡激动剂BAD失活介导的线粒体凋亡抑制，以激酶活性依赖的方式促进癌细胞的存活。这些观察结果确定STK33为治疗由突变型KRAS驱动的癌症的靶点，并证明了RNAi筛选在发现由致癌突变产生的功能依赖性方面的潜力，这些依赖性可能使针对具有“不可成药”基因改变的癌症进行治疗干预成为可能。
