STK33 Kinase Activity Is Nonessential in KRAS-Dependent Cancer Cells
STK33 Kinase Activity Is Nonessential in KRAS-Dependent Cancer Cells
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DOI：
10.1158/0008-5472.can-11-0778
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发表时间：
2011-09-01
期刊：
影响因子：
11.2
通讯作者：
Dussault, Isabelle
中科院分区：
文献类型：
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作者：
Babij, Carol;Zhang, Yihong;Dussault, Isabelle
尽管KRAS突变在人类癌症中普遍存在，但仍然没有靶向治疗方法。已提出丝氨酸-苏氨酸激酶STK 33是突变型KRAS依赖性细胞系存活所需的，表明STK 33的小分子激酶抑制剂可用于治疗KRAS依赖性肿瘤。在这项研究中，我们使用RNA干扰、显性突变过表达和小分子抑制剂研究了STK 33在突变KRAS人类癌细胞中的作用。正如预期的那样，KRAS下调降低了KRAS依赖性细胞的存活率。相反，STK 33下调或显性突变体过表达对KRAS信号传导或这些细胞的存活没有影响。类似地，在一组广泛的KRAS野生型或突变细胞中进行的合成致死siRNA筛选鉴定出KRAS而不是STK 33是生存所必需的。我们还获得了类似的负面结果，使用小分子抑制剂的STK 33激酶鉴定的高通量筛选。综上所述，我们的研究结果反驳了早期的提议，即STK 33抑制可能是靶向人类KRAS突变肿瘤的有用治疗方法。Cancer Res; 71（17）; 5818-26.（C）2011年《非洲标准化评论》。
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. Cancer Res; 71(17); 5818-26. (C)2011 AACR.