Vorinostat boosts lung cancer TKI sensitivity
medwireNews: Preliminary research suggests it is possible to overcome tyrosine kinase inhibitor (TKI) resistance in epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC).
A team of Japanese scientists reports that the histone deacetylase (HDAC) inhibitor vorinostat restored sensitivity to the EGFR-TKI gefitinib in a EGFR-mutant cell line carrying a second loss-of-function mutation to a proapoptotic protein.
The deletion in the BIM gene - a member of the Bcl-2 protein family required for TKI-induced apoptosis - affects 12.9% of the East Asian population and is associated with poor response to gefitinib or erlotinib treatment in NSCLC patients, explain Seiji Yano (Kanazawa University, Ishikawa) and co-workers.
"Our findings illustrate the importance of clinical trials testing the ability of combinations of vorinostat and EGFR-TKIs to overcome EGFR-TKI resistance associated with the BIM polymorphism in patients with EGFR-mutant NSCLC," they say.
As reported in Cancer Research, the team confirmed clinical reports of poor TKI sensitivity in patients carrying the BIM deletion polymorphism. Wild-type cell lines exposed to gefitinib had a significant increase in BIM expression and caspase-3/7 activity, leading to apoptosis; no such response occurred in BIM deletion cell lines.
Vorinostat treatment induced a dose-dependent increase in the proapoptotic form of BIM and acetylated histone H3 in EGFR-mutant NSCLC cells with and without the BIM deletion polymorphism.
Combined treatment with vorinostat and gefitinib led to a significant increased expression of proapopotic form of BIM, mediating gefitinib-induced caspase-3/7 activity.
Furthermore, in a mouse xenograft model, treatment with gefitinib plus vorinostat induced significant tumor regression in EGFR-mutant tumors carrying the BIM mutation, compared with only a slight slowing of tumor growth with gefitinib or vorinostat alone.
Yano et al note that the BIM deletion polymorphism can be easily detected in patient samples of tumor, peripheral blood, and serum, and that vorinostat has US Food and Drug Administration approval as a treatment for advanced lymphoma.
"Therefore, the combination of gefitinib and vorinostat could easily be tested clinically," they say.
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