Acquired Resistance to the Hsp90 Inhibitor, Ganetespib, in <i>KRAS-</i>Mutant NSCLC Is Mediated via Reactivation of the ERK-p90RSK-mTOR Signaling Network.

ABSTRACT: Approximately 25% of non-small cell lung cancer (NSCLC) patients have KRAS mutations, and no effective therapeutic strategy exists for these patients. The use of Hsp90 inhibitors in KRAS-mutant NSCLC appeared to be a promising approach, as these inhibitors target many KRAS downstream effectors; however, limited clinical efficacy has been observed due to resistance. Here, we examined the mechanism(s) of acquired resistance to the Hsp90 inhibitor, ganetespib, and identified novel and rationally devised Hsp90 inhibitor combinations, which may prevent and overcome resistance to Hsp90 inhibitors. We derived KRAS-mutant NSCLC ganetespib-resistant cell lines to identify the resistance mechanism(s) and identified hyperactivation of RAF/MEK/ERK/RSK and PI3K/AKT/mTOR pathways as

SUBMITTER: Chatterjee S 

PROVIDER: S-EPMC5418121 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature