Reactivation of the p90RSK-CDC25C Pathway Leads to Bypass of the Ganetespib-Induced G₂-M Arrest and Mediates Acquired Resistance to Ganetespib in KRAS-Mutant NSCLC.

ABSTRACT: A subset of non-small cell lung cancers (NSCLC) are dependent upon oncogenic driver mutations, including the most frequently observed driver mutant KRAS, which is associated with a poor prognosis. As direct RAS targeting in the clinic has been unsuccessful to date, use of Hsp90 inhibitors appeared to be a promising therapy for KRAS-mutant NSCLC; however, limited clinical efficacy was observed due to rapid resistance. Furthermore, the combination of the Hsp90 inhibitor (Hsp90i), ganetespib, and docetaxel was tested in a phase III clinical trial and failed to demonstrate benefit. Here, we investigated the mechanism(s) of resistance to ganetespib and explored why the combination with docetaxel failed in the clinic. We have not only identified a critical role for the bypass of th

SUBMITTER: Chatterjee S 

PROVIDER: S-EPMC5544554 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature