Ubiquitin enzymes show lung cancer treatment promise
medwireNews: Deubiquitinating enzymes (DUBs) offer a novel target for the treatment of lung cancer through the receptor tyrosine kinase (RTK) signaling pathway, scientists say.
Zigang Dong (University of Minnesota, Austin, USA) and co-authors used a small interfering RNA to knockdown ubiquitin-specific peptidase (USP)8 expression in non-small-cell lung cancer (NSCLC) cell lines resistant to the epidermal growth factor receptor (EGFR) inhibitor gefitinib, resulting in a significant reduction in cell viability.
By contrast, USP8 knockdown had no impact on the viability of healthy bronchial epithelial, human lung fibroblast, or primary dermal fibroblast cell lines.
The team followed this by using a small molecular inhibitor to downregulate protein expression of the key RTKs EGFR, ERBB2, ERBB3, and MET in NSCLC cell lines.
The USP8 inhibitor also reduced cell viability of both gefitinib-resistant and -sensitive NSCLC cells by blocking the RTK pathway without affecting healthy cell lines, Dong et al report in Clinical Cancer Research.
Moreover, in a mouse xenograft model, the USP8 inhibitor significantly reduced both gefitinib-resistant and -sensitive tumor growth compared with control mice. Tumor analysis confirmed that the USP8 inhibitor reduced expression of phosphorylated EGFR, ERBB3, and c-MET.
"These observations provide proof-of-principle that targeting USP8 can selectively kill cancer cells without adverse effects on normal cells," report Dong et al.
"More specifically, our data suggest that inhibition of USP8 is an effective method for overcoming gefitinib-resistance in [NSCLC]."
The researchers add: "Unlike approaches based on direct receptor-inhibitor concepts, we have shown that manipulation of USP8, an endogenous regulator of such receptors, can cause degradation of these proteins and thereby reduce the likelihood of further resistance emerging through receptor mutation or amplification.
"Our data suggest that USP8 is a promising drug target for gefitinib-resistant lung cancers."
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