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07-05-2013 | Respiratory | Article

Hsp90 inhibitor shows NSCLC promise

Abstract

Free abstract

medwireNews: Treatment with a heatshock protein (Hsp)90 inhibitor may induce loss of EML4-AKL expression in non-small cell lung cancer (NSCLC) cells, preliminary results suggest.

"The bioactivity profile of ganetespib presented here underscores a new therapeutic opportunity to target ALK [anaplastic lymphoma kinase] and overcome multiple mechanisms of resistance in patients with ALK-positive NSCLC," say David Proia (Synta Pharmaceuticals Corp, Lexington, Massachusetts, USA) and co-authors.

As reported in Cancer Discovery, inhibition of Hsp90 disrupts proteins involved in oncogenic signaling pathways in lung adenocarcinoma including the EML4-ALK fusion protein. This is also targeted by the ALK inhibitor crizotinib via a different mechanism.

In the H3122 ALK-positive NSCLC cell line, ganetespib had 30 times greater potency than crizotinib (10 vs 300 nmol/L), and there was complete loss of ALK expression and other tumor markers at a ganetespib dose of 30 nmol/L.

Moreover, ganetespib was effective against ALK-positive lung cancer cell lines with resistance to crizotinib therapy.

Using mice with H3122 ALK-positive NSCLC cancer xenografts, the researchers then compared ganetespib and crozitinb treatment, and found the Hsp90 inhibitor had greater anti-tumor efficacy than the ALK inhibitor and significantly prolonged mouse survival.

In a clinical trial of eight crozitinib-naïve patients, treatment with ganetespib achieved four partial responses and three patients had stable disease after 16 weeks, with just one patient experiencing progression.

"The 50% objective response rate combined with the overall 88% disease control rate within this subset, therefore, provides clinical validation for the therapeutic potential of ganetespib in ALK+ NSCLC," say the researchers.

They also observed tumor shrinkage after ganetespib therapy in a NSCLC patient who developed resistance to crozitinib after a year of treatment and had a secondary ALK mutation.

"Ganetespib therapy represents a new option for treating ALK-dependent lung cancer in sequence with direct ALK inhibitors and/or for treating patients who relapse following direct ALK inhibitor therapy," said Proia in a press release.

medwireNews (www.medwirenews.com) is an independent clinical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2013

By Lynda Williams, Senior medwireNews Reporter

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