Ganetespib (STA-9090), a nongeldanamycin HSP90 inhibitor, has potent antitumor activity in in vitro and in vivo models of non-small cell lung cancer.
OBJECTIVE
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.


METHODS
The activity of ganetespib was compared with 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 cochaperone, 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 IC(50) values ranging 2 to 30 nmol/L, substantially lower than those required for 17-AAG (20-3,500 nmol/L). 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 t(1/2) 58.3 hours, supporting once-weekly dosing experiments, in which ganetespib produced greater tumor growth inhibition than 17-AAG. However, after a single dose, reexpression of mutant EGFR occurred by 72 hours, correlating with reversal of antiproliferative and proapoptotic effects. Consecutive day dosing resulted in xenograft regressions, accompanied by more sustained pharmacodynamic effects. Ganetespib also showed 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.
Department of Molecular Pharmacology and Therapeutics, Oncology Institute, Loyola University of Chicago, Stritch School of Medicine, Maywood, Illinois, USA.
Takeshi
T
Shimamura
Samanthi A
SA
Perera
Kevin P
KP
Foley
Jim
J
Sang
Scott J
SJ
Rodig
Takayo
T
Inoue
Liang
L
Chen
Danan
D
Li
Julian
J
Carretero
Yu-Chen
YC
Li
Papiya
P
Sinha
Christopher D
CD
Carey
Christa L
CL
Borgman
John-Paul
JP
Jimenez
Matthew
M
Meyerson
Weiwen
W
Ying
James
J
Barsoum
Kwok-Kin
KK
Wong
Geoffrey I
GI
Shapiro
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D016227:Benzoquinones / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D000071876:Prostaglandin-E Synthases; D011485:Protein Binding / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C533237:STA 9090; D014230:Triazoles; C112765:tanespimycin; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases