STK33 Kinase Activity Is Nonessential in KRAS-Dependent Cancer Cells

被引：92

作者：

Babij, Carol ^{[1
]}

Zhang, Yihong ^{[1
]}

Kurzeja, Robert J. ^{[2
]}

Munzli, Anke ^{[3
]}

Shehabeldin, Amro ^{[2
]}

Fernando, Manory ^{[1
]}

Quon, Kim ^{[1
]}

Kassner, Paul D. ^{[3
]}

Ruefli-Brasse, Astrid A. ^{[1
]}

Watson, Vivienne J. ^{[1
]}

Fajardo, Flordeliza ^{[1
]}

Jackson, Angela ^{[1
]}

Zondlo, James ^{[2
]}

Sun, Yu ^{[2
]}

Ellison, Aaron R. ^{[2
]}

Plewa, Cherylene A. ^{[2
]}

San Miguel, Tisha ^{[3
]}

Robinson, John ^{[2
]}

McCarter, John ^{[3
]}

Schwandner, Ralf ^{[3
]}

Judd, Ted ^{[4
]}

Carnahan, Josette ^{[1
]}

Dussault, Isabelle ^{[1
]}

机构：

[1] Amgen Inc, Dept Oncol Res, Thousand Oaks, CA 91320 USA

[2] Amgen Inc, Prot Sci, Thousand Oaks, CA 91320 USA

[3] Amgen Inc, Lead Discovery, Thousand Oaks, CA 91320 USA

[4] Amgen Inc, Med Chem, Thousand Oaks, CA 91320 USA

来源：

CANCER RESEARCH | 2011年 / 71卷 / 17期

关键词：

LUNG-CANCER; MUTATIONS; RAS; CHROMOSOME; INHIBITOR; GEFITINIB; THERAPY; GROWTH;

D O I：

10.1158/0008-5472.CAN-11-0778

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：5818 / 5826

页数：9

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