Garon, Edward B., Finn, Richard S., Hamidi, Habib, Dering, Judy, Kamranpour, Naeimeh, Desai, Amrita J., Hosmer, Wylie, Dubinett, Steven M., Slamon, Dennis J., Ide, Susan, Avsar, Emin, Jensen, Michael Rugaard, Quadt, Cornelia and Liu, Manway (2013) The HSP90 inhibitor NVP-AUY922 potently inhibits non-small cell lung cancer growth. Molecular cancer therapeutics, 12 (6). pp. 890-900. ISSN 1538-8514

Abstract

Heat shock protein 90 (HSP90) is involved in protein folding and functions as a chaperone for client proteins, many of which are important in non-small cell lung cancer (NSCLC) pathogenesis. We sought to define effects of the HSP90 inhibitor NVP-AUY922 in NSCLC cell lines, and identify predictors of response by in vitro and in vivo evaluation. NVP-AUY922 potently inhibited growth in all 41 NSCLC cell lines evaluated in vitro with IC50 < 100 nM. In 36 lines, IC100 (complete inhibition of proliferation) was below 40 nM. Greatest sensitivity was in lines with low baseline HSP70 protein levels. In vitro comparison of gene expression before and after NVP-AUY922 exposure demonstrated consistent changes in expression of genes involved in a wide range of cellular functions, including consistently decreased expression of dihydrofolate reductase after exposure. Expression of the co-chaperone AHA1 increased in response to exposure, and this effect was disproportionately seen in less sensitive lines. NVP-AUY922 slowed growth of A549 (KRAS mutant) xenografts, and achieved tumor stability and decreased epidermal growth factor receptor (EGFR) protein expression in H1975 xenografts, a model harboring a sensitizing and a resistance mutation for EGFR tyrosine kinase inhibitors in the EGFR gene. This impressive preclinical efficacy in a broad range of NSCLC cell lines led to clinical evaluation of NVP-AUY922 in NSCLC patients with tumors bearing known driver mutations as well as tumors without such abnormalities. An ongoing phase II NSCLC trial will incorporate correlative data to confirm our observations and guide further development of NVP-AUY922 in NSCLC.
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Item Type:	Article
Date Deposited:	26 Apr 2016 23:46
Last Modified:	26 Apr 2016 23:46
URI:	https://oak.novartis.com/id/eprint/7810