Targeting KRAS Mutant Non-Small Cell Lung Cancer with the Hsp90 Inhibitor Ganetespib

Abstract

Mutant KRAS is a feature of over 25% of non-small cell lung cancers (NSCLC) and represents one of the most prevalent oncogenic drivers in this disease. NSCLC tumors with oncogenic KRAS respond poorly to current therapies necessitating the pursuit of new treatment strategies. Targeted inhibition of the molecular chaperone heat shock protein 90 (Hsp90) results in the coordinated blockade of multiple oncogenic signaling pathways in tumor cells, and has thus emerged as an attractive avenue for therapeutic intervention in human malignancies. Here we examined the activity of ganetespib, a small molecule inhibitor of Hsp90 currently in clinical trials for NSCLC, in a panel of lung cancer cell lines harboring a diverse spectrum of KRAS mutations. In vitro, ganetespib was potently cytotoxic in all lines, with concomitant destabilization of KRAS signaling effectors. Combinations of low dose ganetespib with MEK or PI3K/mTOR inhibitors resulted in superior cytotoxic activity than single agents alone in a subset of mutant KRAS cells, and the antitumor efficacy of ganetespib was potentiated by co-treatment with the PI3K/mTOR inhibitor BEZ235 in A549 xenografts in vivo. At the molecular level ganetespib suppressed activating feedback signaling loops that occurred in response to MEK and PI3K/mTOR inhibition, although this activity was not the sole determinant of combinatorial benefit. In addition, ganetespib sensitized mutant KRAS NSCLC cells to standard of care chemotherapeutics of the anti-mitotic, topoisomerase inhibitor and alkylating agent classes. Taken together, these data underscore the promise of ganetespib as a single agent or combination treatment in KRAS-driven lung tumors.