Department of Oncology Research, Amgen Inc., Thousand Oaks, California, USA.
Cancer Res. 2011 Sep 1;71(17):5818-26. doi: 10.1158/0008-5472.CAN-11-0778. Epub 2011 Jul 8.
Despite the prevalence of KRAS mutations in human cancers, there remain no targeted therapies for treatment. The serine-threonine kinase STK33 has been proposed to be required for the survival of mutant KRAS-dependent cell lines, suggesting that small molecule kinase inhibitors of STK33 may be useful to treat KRAS-dependent tumors. In this study, we investigated the role of STK33 in mutant KRAS human cancer cells using RNA interference, dominant mutant overexpression, and small molecule inhibitors. As expected, KRAS downregulation decreased the survival of KRAS-dependent cells. In contrast, STK33 downregulation or dominant mutant overexpression had no effect on KRAS signaling or survival of these cells. Similarly, a synthetic lethal siRNA screen conducted in a broad panel of KRAS wild-type or mutant cells identified KRAS but not STK33 as essential for survival. We also obtained similar negative results using small molecule inhibitors of the STK33 kinase identified by high-throughput screening. Taken together, our findings refute earlier proposals that STK33 inhibition may be a useful therapeutic approach to target human KRAS mutant tumors.
尽管 KRAS 突变在人类癌症中普遍存在，但目前仍没有针对该突变的靶向治疗方法。丝氨酸-苏氨酸激酶 STK33 被认为是依赖突变型 KRAS 的细胞系生存所必需的，这表明 STK33 的小分子激酶抑制剂可能对治疗依赖 KRAS 的肿瘤有用。在这项研究中，我们使用 RNA 干扰、显性突变体过表达和小分子抑制剂来研究 STK33 在依赖突变型 KRAS 的人类癌细胞中的作用。不出所料，KRAS 的下调降低了依赖 KRAS 的细胞的存活率。相比之下，STK33 的下调或显性突变体过表达对这些细胞的 KRAS 信号或存活没有影响。同样，在广泛的 KRAS 野生型或突变型细胞系中进行的合成致死性 siRNA 筛选鉴定出 KRAS 是这些细胞存活所必需的，而不是 STK33。我们还使用高通量筛选鉴定的 STK33 激酶的小分子抑制剂得到了类似的阴性结果。综上所述，我们的研究结果推翻了之前关于 STK33 抑制可能是一种针对人类 KRAS 突变肿瘤的有效治疗方法的建议。
