Targeting of KRAS mutant tumors by HSP90 inhibitors involves degradation of STK33
Activating mutations in the KRAS protooncogene occur in about 30% of all human tumors and predict failure of response to molecularly targeted therapies such as inhibitors of the epithelial growth factor receptor (EGFR). Whereas efforts to target mutant KRAS directly have not yet been successful in the clinic, strategies to target KRAS indirectly by blocking its downstream effectors are currently being tested in clinical trials.
Scholl and colleagues (Scholl et al., Cell, 2009) recently observed in KRAS mutant human tumor cells an enhanced dependence on STK33, a functionally uncharacterized serine/threonine kinase and suggested STK33 as an attractive target for therapy.
In the present study, Azoitei and colleagues demonstrated that STK33 is associated with and stabilized by components of the HSP90 chaperone complex in human cancer cells. Inhibition of HSP90 induces the proteasome-mediated degradation of STK33, resulting in apoptosis, preferentially in tumor cells harboring mutant KRAS. Furthermore, pharmacologic HSP90 inhibition impairs growth of mutant KRAS-dependent tumors in vivo in an STK33-dependent manner. Thus, a strong requirement for STK33 may be used to target mutant KRAS-driven cancers and the subset of patients who benefit from HSP90 inhibitors might be enriched for cases codependent on mutant KRAS and STK33.
http://www.ncbi.nlm.nih.gov/pubmed/22451720