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.
authors.affiliation: Department of Internal Medicine III, Ulm University, 89081 Ulm, Germany.
authors.forename: Ninel
authors.initials: N
authors.lastname: Azoitei
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Hoffmann
authors.forename: Jana M
authors.initials: JM
authors.lastname: Ellegast
authors.forename: Claudia R
authors.initials: CR
authors.lastname: Ball
authors.forename: Kerstin
authors.initials: K
authors.lastname: Obermayer
authors.forename: Ulrike
authors.initials: U
authors.lastname: Gößele
authors.forename: Britta
authors.initials: B
authors.lastname: Koch
authors.forename: Katrin
authors.initials: K
authors.lastname: Faber
authors.forename: Felicitas
authors.initials: F
authors.lastname: Genze
authors.forename: Mark
authors.initials: M
authors.lastname: Schrader
authors.forename: Hans A
authors.initials: HA
authors.lastname: Kestler
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.forename: Gabriela
authors.initials: G
authors.lastname: Chiosis
authors.forename: Hanno
authors.initials: H
authors.lastname: Glimm
authors.forename: Stefan
authors.initials: S
authors.lastname: Fröhling
authors.forename: Claudia
authors.initials: C
authors.lastname: Scholl
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000502:physiology; D016283:Proto-Oncogene Proteins p21(ras); D054875:Ubiquitination; D018631:ras Proteins / Q000235:genetics* / Q000502:physiology
chemical_list: D018841:HSP90 Heat-Shock Proteins; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D017346:Protein Serine-Threonine Kinases; C505233:STK33 protein, human; D046988:Proteasome Endopeptidase Complex; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins