Synergy Between the Novel Hsp90 Inhibitor STA-9090 and Taxanes in Preclinical Models of NSCLC

The molecular chaperone heat shock protein 90 (Hsp90) plays a key role in regulating the correct folding, stability and activity of many important signal transduction molecules that have been implicated in the pathophysiology of non-small cell lung cancer (NSCLC), including: BRAF, EGFR, HER2, MET and VEGFR. STA-9090 is a novel small molecule Hsp90 inhibitor that is structurally unrelated to the first-generation anasamycin Hsp90 inhibitors 17-AAG and IPI-504. STA-9090 competes with ATP for binding to the N-terminal domain of Hsp90, thereby inducing proteasome-mediated degradation of Hsp90 client proteins preferentially in cancer versus normal cells. STA-9090 is currently being evaluated in multiple Phase 1 and Phase 2 clinical trials in solid tumor and hematological malignancies, as well as in an open-label, multi-center Phase 2 clinical trial in patients with advanced NSCLC that harbor wild type or activated forms of EGFR and KRAS. We have investigated the activity of STA-9090 alone and in combination with taxanes in preclinical NSCLC models. In vitro, STA-9090 potently inhibited cell proliferation in 24/24 human NSCLC cell lines (median IC50 = 6.5 nM; range 1-31 nM), irrespective of EGFR, HER2 or KRAS mutational status. STA-9090 was also active against cell lines that displayed resistance to erlotinib and/or 17-AAG