Acquired resistance to the Hsp90 inhibitor ganetespib in KRAS mutant NSCLC is mediated via reactivation of the ERK–p90RSK–mTOR signaling network

摘要

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 Heat shock protein 90 (Hsp90) inhibitors in KRAS mutant NSCLC appeared to be a promising approach since 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 (GR) cell lines to identify the resistance mechanism(s) and identified hyperactivation of RAF/MEK/ERK/RSK and PI3K/AKT/mTOR pathways as key resistance mechanisms. Furthermore, we found that GR cells are “addicted” to these pathways as ganetespib resistance lead to synthetic lethality to a dual PI3K/mTOR, a PI3K, or an ERK inhibitor. Interestingly, the levels and activity of a key activator of the mTOR pathway and an ERK downstream target, p90 ribosomal S6 kinase (RSK) were also increased in the GR cells. Genetic or pharmacologic inhibition of p90RSK in GR cells restored sensitivity to ganetespib, whereas p90RSK overexpression induced ganetespib resistance in naïve cells, validating p90RSK as a mediator of resistance and a novel therapeutic target. Our studies offer a way forward for Hsp90 inhibitors through the rational design of Hsp90 inhibitor combinations that may prevent and/or overcome resistance to Hsp90 inhibitors providing an effective therapeutic strategy for KRAS mutant NSCLC.