1. Kinome-wide RNAi studies in human multiple myeloma identify vulnerable kinase targets, including a lymphoid-restricted kinase, GRK6.
- Author
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Tiedemann RE, Zhu YX, Schmidt J, Yin H, Shi CX, Que Q, Basu G, Azorsa D, Perkins LM, Braggio E, Fonseca R, Bergsagel PL, Mousses S, and Stewart AK
- Subjects
- Animals, Cell Line, Tumor, Chromosomes, Human genetics, Chromosomes, Human metabolism, G-Protein-Coupled Receptor Kinases antagonists & inhibitors, G-Protein-Coupled Receptor Kinases genetics, Gene Silencing drug effects, HSP90 Heat-Shock Proteins genetics, HSP90 Heat-Shock Proteins metabolism, Humans, Mice, Multiple Myeloma drug therapy, Multiple Myeloma genetics, Phosphorylation drug effects, Phosphorylation genetics, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Protein Kinases genetics, Protein Kinases metabolism, STAT3 Transcription Factor genetics, STAT3 Transcription Factor metabolism, Translocation, Genetic drug effects, Translocation, Genetic genetics, G-Protein-Coupled Receptor Kinases metabolism, Multiple Myeloma enzymology, RNA, Small Interfering
- Abstract
A paucity of validated kinase targets in human multiple myeloma has delayed clinical deployment of kinase inhibitors in treatment strategies. We therefore conducted a kinome-wide small interfering RNA (siRNA) lethality study in myeloma tumor lines bearing common t(4;14), t(14;16), and t(11;14) translocations to identify critically vulnerable kinases in myeloma tumor cells without regard to preconceived mechanistic notions. Fifteen kinases were repeatedly vulnerable in myeloma cells, including AKT1, AK3L1, AURKA, AURKB, CDC2L1, CDK5R2, FES, FLT4, GAK, GRK6, HK1, PKN1, PLK1, SMG1, and TNK2. Whereas several kinases (PLK1, HK1) were equally vulnerable in epithelial cells, others and particularly G protein-coupled receptor kinase, GRK6, appeared selectively vulnerable in myeloma. GRK6 inhibition was lethal to 6 of 7 myeloma tumor lines but was tolerated in 7 of 7 human cell lines. GRK6 exhibits lymphoid-restricted expression, and from coimmunoprecipitation studies we demonstrate that expression in myeloma cells is regulated via direct association with the heat shock protein 90 (HSP90) chaperone. GRK6 silencing causes suppression of signal transducer and activator of transcription 3 (STAT3) phosphorylation associated with reduction in MCL1 levels and phosphorylation, illustrating a potent mechanism for the cytotoxicity of GRK6 inhibition in multiple myeloma (MM) tumor cells. As mice that lack GRK6 are healthy, inhibition of GRK6 represents a uniquely targeted novel therapeutic strategy in human multiple myeloma.
- Published
- 2010
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