Synergistic activity of the Hsp90 inhibitor ganetespib with taxanes in non-small cell lung cancer models.
Systemic chemotherapy using two-drug platinum-based regimens for the treatment of advanced stage non-small cell lung cancer (NSCLC) has largely reached a plateau of effectiveness. Accordingly, efforts to improve survival and quality of life outcomes have more recently focused on the use of molecularly targeted agents, either alone or in combination with standard of care therapies such as taxanes. The molecular chaperone heat shock protein 90 (Hsp90) represents an attractive candidate for therapeutic intervention, as its inhibition results in the simultaneous blockade of multiple oncogenic signaling cascades. Ganetespib is a non-ansamycin inhibitor of Hsp90 currently under clinical evaluation in a number of human malignancies, including NSCLC. Here we show that ganetespib potentiates the cytotoxic activity of the taxanes paclitaxel and docetaxel in NSCLC models. The combination of ganetespib with paclitaxel, docetaxel or another microtubule-targeted agent vincristine resulted in synergistic antiproliferative effects in the H1975 cell line in vitro. These benefits translated to improved efficacy in H1975 xenografts in vivo, with significantly enhanced tumor growth inhibition observed in combination with paclitaxel and tumor regressions seen with docetaxel. Notably, concurrent exposure to ganetespib and docetaxel improved antitumor activity in 5 of 6 NSCLC xenograft models examined. Our data suggest that the improved therapeutic indices are likely to be mechanistically multifactorial, including loss of pro-survival signaling and direct cell cycle effects resulting from Hsp90 modulation by ganetespib. Taken together, these findings provide preclinical evidence for the use of this combination to treat patients with advanced NSCLC.
Synta Pharmaceuticals Corp., Lexington, MA 02421, USA. DProia@syntapharma.com
David A
DA
Proia
Jim
J
Sang
Suqin
S
He
Donald L
DL
Smith
Manuel
M
Sequeira
Chaohua
C
Zhang
Yuan
Y
Liu
Shuxia
S
Ye
Dan
D
Zhou
Ronald K
RK
Blackman
Kevin P
KP
Foley
Keizo
K
Koya
Yumiko
Y
Wada
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000077143:Docetaxel; D004338:Drug Combinations; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D017239:Paclitaxel / Q000008:administration & dosage*; D043823:Taxoids / Q000008:administration & dosage*; D014230:Triazoles / Q000008:administration & dosage*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004338:Drug Combinations; D018841:HSP90 Heat-Shock Proteins; C533237:STA 9090; D043823:Taxoids; D014230:Triazoles; D000077143:Docetaxel; D017239:Paclitaxel