Ganetespib (STA-9090), a Nongeldanamycin HSP90 Inhibitor, Has Potent Antitumor Activity in In Vitro and In Vivo Models of Non–Small Cell Lung Cancer

Abstract

Purpose We describe the anticancer activity of ganetespib, a novel non-geldanamycin heat shock protein 90 (HSP90) inhibitor, in non-small cell lung cancer (NSCLC) models. Experimental Design The activity of ganetespib was compared to that of the geldanamycin 17-AAG in biochemical assays, cell lines and xenografts, and evaluated in an ERBB2 YVMA-driven mouse lung adenocarcinoma model. Results Ganetespib blocked the ability of HSP90 to bind to biotinylated geldanamycin and disrupted the association of HSP90 with its co-chaperone, p23, more potently than 17-AAG. In genomically-defined NSCLC cell lines, ganetespib caused depletion of receptor tyrosine kinases, extinguishing of downstream signaling, inhibition of proliferation and induction of apoptosis with IC50 values ranging 2–30 nM, substantially lower than those required for 17-AAG (20– 3,500 nM). Ganetespib was also approximately 20-fold more potent in isogenic Ba/F3 pro-B cells rendered IL-3 independent by expression of EGFR and ERBB2 mutants. In mice bearing NCI-H1975 (EGFR L858R/T790M) xenografts, ganetespib was rapidly eliminated from plasma and normal tissues but was maintained in tumor with t1/2 58.3 hours, supporting once-weekly dosing experiments, in which ganetespib produced greater tumor growth inhibition than 17-AAG. However, after a single dose, re-expression of mutant EGFR occurred by 72 hours, correlating with reversal of anti-proliferative and pro-apoptotic effects. Consecutive day dosing resulted in xenograft regressions, accompanied by more sustained pharmacodynamic effects. Ganetespib also demonstrated activity against mouse lung adenocarcinomas driven by oncogenic ERBB2 YVMA. Conclusions Ganetespib has greater potency than 17-AAG and potential efficacy against several NSCLC subsets, including those harboring EGFR or ERBB2 mutation.

TAS-116, a Highly Selective Inhibitor of Heat Shock Protein 90α and β, Demonstrates Potent Antitumor Activity and Minimal Ocular Toxicity in Preclinical Models

“…3A and Supplementary Fig. S1), as previously reported (9,11,35,36), TAS-116 was more rapidly eliminated from retina (t 1/2 ¼ 3.4 hours) than the other HSP90 inhibitors (t 1/2 ¼ 7.1-19.1 hours), thereby demonstrating its lower retinal distribution profile (Fig. 3A and Supplementary Table S3).…”

HSP90 Inhibitor–SN-38 Conjugate Strategy for Targeted Delivery of Topoisomerase I Inhibitor to Tumors

“…While we cannot rule out a contribution of direct chaperone inhibitory effects by STA-12-8666, these were unlikely exerting a major influence as evidenced by the compounds' weak intrinsic HSP90 inhibitory activity, as well as the superior efficacy achieved when compared with irinotecan plus ganetespib combination therapy. Further evidence was provided by the comparatively weaker antiproliferative effects of STA-12-8666 on tumor lines in vitro relative to ganetespib, yet the robust tumor regressions seen in xenograft lung tumors in vivo exceeded ganetespibs' previously published antitumor activity in the same models (31,32). Thus, our findings clearly demonstrate that HDC-mediated delivery of an established cytotoxic agent can achieve dramatic improvements in efficacy over traditional clinical formulations for these agents and that the approach is not complicated by effects due to loss of HSP90 function.…”

“…We applied these fundamentals to establish a new drug delivery system termed HSP90 inhibitor-drug conjugates, or HDC, based on the property that small-molecule inhibitors of HSP90 are preferentially retained in tumor cells in contrast to their rapid clearance from the circulation and normal tissues (8)(9)(10)(11)(12). HSP90 is a highly conserved molecular chaperone that plays an indispensable role in regulating the maturation and functional stability of a vast repertoire of cellular client proteins (13).…”

Plasma Levels of Heat Shock Protein 90 Alpha Associated with Lung Cancer Development and Treatment Responses

“…Indeed, Hsp90a protein was one of 12 proteins used as a panel for lung cancer diagnosis, which were generated by a new aptamer-based proteomic analysis of 1,326 archived serum samples from four independent studies of NSCLC in long-term tobacco-exposed populations (16). Other previous studies showed the HSP90 inhibitor had a potent antitumor activity in in vitro and in vivo models of therapy against NSCLC (17,18). Our current study further demonstrates that detection of plasma Hsp90a protein could be useful as a biomarker for diagnosis of lung cancer and for therapeutic monitoring of responses of patients with lung cancer.…”