Targeting of KRAS mutant tumors by HSP90 inhibitors involves degradation of STK33 Journal Article
| Authors: | Azoitei, N.; Hoffmann, C. M.; Ellegast, J. M.; Ball, C. R.; Obermayer, K.; Gößele, U.; Koch, B.; Faber, K.; Genze, F.; Schrader, M.; Kestler, H. A.; Döhner, H.; Chiosis, G.; Glimm, H.; Frohling, S.; Scholl, C. |
| Article Title: | Targeting of KRAS mutant tumors by HSP90 inhibitors involves degradation of STK33 |
| Abstract: | Previous efforts to develop drugs that directly inhibit the activity of mutant KRAS, the most commonly mutated human oncogene, have not been successful. Cancer cells driven by mutant KRAS require expression of the serine/threonine kinase STK33 for their viability and proliferation, identifying STK33 as a context-dependent therapeutic target. However, specific strategies for interfering with the critical functions of STK33 are not yet available. Here, using a mass spectrometry-based screen for STK33 protein interaction partners, we report that the HSP90/CDC37 chaperone complex binds to and stabilizes STK33 in human cancer cells. Pharmacologic inhibition of HSP90, using structurally divergent small molecules currently in clinical development, induced proteasome-mediated degradation of STK33 in human cancer cells of various tissue origin in vitro and in vivo, and triggered apoptosis preferentially in KRAS mutant cells in an STK33-dependent manner. Furthermore, HSP90 inhibitor treatment impaired sphere formation and viability of primary human colon tumor-initiating cells harboring mutant KRAS. These findings provide mechanistic insight into the activity of HSP90 inhibitors in KRAS mutant cancer cells, indicate that the enhanced requirement for STK33 can be exploited to target mutant KRAS-driven tumors, and identify STK33 depletion through HSP90 inhibition as a biomarker-guided therapeutic strategy with immediate translational potential. © 2012 Azoitei et al. |
| Keywords: | controlled study; unclassified drug; oncoprotein; human cell; genetics; mutation; proto-oncogene proteins; nonhuman; drug targeting; protein function; mouse; metabolism; apoptosis; proteasome; proteasome endopeptidase complex; protein degradation; protein protein interaction; animal experiment; animal model; colonic neoplasms; drug effect; pathology; cell line, tumor; protein serine threonine kinase; physiology; drug antagonism; ubiquitination; drug mechanism; protein-serine-threonine kinases; colon cancer; colon tumor; tumor cell line; heat shock protein 90 inhibitor; pu h71; tanespimycin; heat shock protein 90; hsp90 heat-shock proteins; ras protein; ras proteins; oncogene k ras; k ras protein; kras protein, human; chaperone; cell cycle protein 37; stk33 protein, human; serine threonine kinase 33 |
| Journal Title: | Journal of Experimental Medicine |
| Volume: | 209 |
| Issue: | 4 |
| ISSN: | 0022-1007 |
| Publisher: | Rockefeller University Press |
| Date Published: | 2012-04-09 |
| Start Page: | 697 |
| End Page: | 711 |
| Language: | English |
| DOI: | 10.1084/jem.20111910 |
| PROVIDER: | scopus |
| PMCID: | PMC3328372 |
| PUBMED: | 22451720 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 24 August 2012" - "CODEN: JEMEA" - "Source: Scopus" |
