Abstract
Mutant KRAS is a feature of more than 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 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 NSCLCs 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 cotreatment 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 antimitotic, 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.
Highlights
Lung cancer is the leading cause of cancer death worldwide [1], and non–small cell lung cancer (NSCLC) accounts for 85% of all cases
The cytotoxic activity of ganetespib was initially evaluated in a panel of 20 NSCLC cell lines selected for expression of known KRAS mutations, including G12, G13, and Q61 variants (Table 1)
As targeted degradation of client proteins is a feature of Hsp90 inhibition, we examined expression changes in client and signaling pathway proteins associated with NSCLC progression
Summary
Lung cancer is the leading cause of cancer death worldwide [1], and non–small cell lung cancer (NSCLC) accounts for 85% of all cases. Intensive research into the underlying biologic and molecular basis of NSCLCs has provided critical insights into essential oncogenic pathways that become dysregulated during tumorigenesis and, in turn, has identified important targets for drug development. These findings have subsequently translated into significant clinical advances due to the inclusion of molecularly targeted agents in novel therapeutic strategies for this disease [5]. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).
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