title: STK33 kinase activity is nonessential in KRAS-dependent cancer cells.
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.
authors: Department of Oncology Research, Amgen Inc., Thousand Oaks, California, USA.
authors: Carol
authors: C
authors: Babij
authors: Yihong
authors: Y
authors: Zhang
authors: Robert J
authors: RJ
authors: Kurzeja
authors: Anke
authors: A
authors: Munzli
authors: Amro
authors: A
authors: Shehabeldin
authors: Manory
authors: M
authors: Fernando
authors: Kim
authors: K
authors: Quon
authors: Paul D
authors: PD
authors: Kassner
authors: Astrid A
authors: AA
authors: Ruefli-Brasse
authors: Vivienne J
authors: VJ
authors: Watson
authors: Flordeliza
authors: F
authors: Fajardo
authors: Angela
authors: A
authors: Jackson
authors: James
authors: J
authors: Zondlo
authors: Yu
authors: Y
authors: Sun
authors: Aaron R
authors: AR
authors: Ellison
authors: Cherylene A
authors: CA
authors: Plewa
authors: Miguel Tisha
authors: MT
authors: San
authors: John
authors: J
authors: Robinson
authors: John
authors: J
authors: McCarter
authors: Ralf
authors: R
authors: Schwandner
authors: Ted
authors: T
authors: Judd
authors: Josette
authors: J
authors: Carnahan
authors: Isabelle
authors: I
authors: Dussault
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D034622:RNA Interference; D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D017346:Protein Serine-Threonine Kinases; C551917:STK32B protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins