Abstract
Inhibition of heat shock protein 90 (Hsp90) abrogates signaling of multiple aberrantly activated oncogenic proteins simultaneously, particularly mutated or amplified kinases, which provides an attractive approach for cancer treatment. Here, we described that FS-93, a potent Hsp90 inhibitor, impacted the survival of several types of oncogene addicted cancer cells through inducing G2/M arrest and apoptosis. Mechanistically, FS-93 treatment triggered the degradation of key client proteins such as HER2, EML4-ALK and c-Met and thereby abolished their downstream signaling pathways. Importantly, FS-93 alone circumvented MET amplification contributed acquired resistance to EGFR inhibition. Our study implicates that targeting Hsp90 is a promising alternative therapeutic tactic in oncogene addicted and derived resistant cancer cells.
Highlights
Heat shock protein 90 (Hsp90) is a highly conserved and constitutively expressed molecular chaperone that facilitates the folding of client proteins and regulates their stability [1,2,3]
We focused our research on evaluating the effect of FS-93 in several types of oncogene addicted cancer models
We investigated the mechanisms of a novel Hsp90 inhibitor FS-93 in oncogene addicted and derived resistant cancer cells
Summary
Heat shock protein 90 (Hsp90) is a highly conserved and constitutively expressed molecular chaperone that facilitates the folding of client proteins and regulates their stability [1,2,3]. In contrast to other well defined kinase inhibition such as EGFR mutation for gefitinib and EML4-ALK fusion for crizotinib, it’s still not clear whether the effect of Hsp inhibitors in clinic results from the degradation of a more sensitive client protein or general effects on multiple clients [18,19,20,21,22]. Some clinical and experimental investigations have indicated that Hsp inhibitors are most effective in oncogene addicted tumor types where the survival of individual cancer depends on specific driving oncogenes [8, 10, 23, 24]. We have reported that FS-93, an analog of NVP-
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