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.