Abstract
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.
Highlights
KRAS activating mutations are present in approximately 30% of human cancers, making KRAS one of the most frequently mutated oncogenes
STK33 knockdown by RNA interference (RNAi) has no effect on the viability of mutant KRAS-dependent cell lines
To test whether STK33 has a synthetic lethal relationship with mutant KRAS, we transiently transfected KRAS wild-type or mutant cells lines with siRNAs directed at STK33 or KRAS
Summary
KRAS activating mutations are present in approximately 30% of human cancers, making KRAS one of the most frequently mutated oncogenes. Multiple preclinical studies in vitro and in vivo have shown that blocking the activity of mutant KRAS is an effective way to inhibit tumor growth, suggesting that drugs that block this pathway could be effective anticancer therapies [1]. Strategies to target KRAS directly, such as downregulating its expression or disrupting its membrane localization through farnesyltransferase inhibitors or geranylgeranyl transferase inhibitors, have not yet been successful in the clinic [2]. Multiple attempts to target KRAS indirectly by blocking its effectors have been undertaken and some are still being tested. Potent and selective inhibitors of MAP/ERK kinase 1/2 (MEK1/2) are currently being tested in several clinical trials (www.clinicaltrials.gov). Authors' Affiliations: 1Department of Oncology Research; 2Protein Sciences; 3Lead Discovery; and 4Medicinal Chemistry, Amgen Inc., Thousand Oaks, California
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