USP8 Is a Novel Target for Overcoming Gefitinib Resistance in Lung Cancer

Abstract

PURPOSE Common treatment modalities for non-small cell lung cancer (NSCLC) involve the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) like gefitinib and erlotinib. However, the vast majority of treated patients acquire resistance to EGFR-TKIs, due in large part to secondary mutations in EGFR or amplification of the MET gene. Our purpose was to test ubiquitin-specific peptidase 8 (USP8) as a potential therapeutic target for gefitinib-resistant and -sensitive non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN Testing the effect of knockdown of USP8 and use of a synthetic USP8 inhibitor to selectively kill gefitinib-resistant (or -sensitive) NSCLCs with little effect on normal cells in cell culture and a xenograft mouse model. RESULTS Knockdown of ubiquitin-specific peptidase 8 (USP8) selectively kills gefitinib-resistant NSCLCs, while having little toxicity toward normal cells. Genetic silencing of USP8 led to the down-regulation of several receptor tyrosine kinases (RTKs), including EGFR, ERBB2, ERBB3, and MET. We also determined that a synthetic USP8 inhibitor markedly decreased the viability of gefitinib-resistant and -sensitive NSCLC cells by decreasing RTK expression, while having no effect on normal cells. Moreover, treatment with a USP8 inhibitor led to significant reductions in tumor size in a mouse xenograft model using gefitinib-resistant and -sensitive NSCLC cells. CONCLUSIONS Our results demonstrate for the first time that the inhibition of USP8 activity or reduction in USP8 expression can selectively kill NSCLC cells. We propose USP8 as a potential therapeutic target for gefitinib-resistant and -sensitive NSCLC cells.

Inhibition of proteasome deubiquitinase activity: a strategy to overcome resistance to conventional proteasome inhibitors?

“…DUBs involved in regulating p53 stability or the cell-surface expression of oncogenic receptors have already been mooted as tempting targets for therapeutic intervention with several candidate drugs already in various stages of pre-clinical development (Byun et al, 2013;Chauhan et al, 2012). In particular targeting proteasome-associated deubiquitination has the potential for increasing the levels of ubiquitin conjugated proteins triggering proteotoxic stress and apoptosis similar to that observed with inhibitors of proteolytic activity.…”

Molecular pathways and therapeutic targets in lung cancer

“…Silencing or pharmacological inhibition of USP8 deubiquitinase, relevant in particular to the stability of RTKs such as EGFR and MET, was shown to induce death of gefitinib-resistant NSCLC cells in vitro and in vivo [52]. …”

USP8: a novel therapeutic target for Cushing’s disease

“…Because EGFR and C-Met have been identified as targets of USP8-related deubiquitination, then modulation of USP8 activity seems to be a preferred choice for resistant patients. Byun et al demonstrated that knockdown of USP8 could decrease the viability of gefitinib-resistant NSCLC cells by down-regulating the expression of RTKs, namely EGFR, ErbB2, ErbB3, and C-Met; moreover, treatment with a synthetic USP8 inhibitor led to significant reductions in tumor size in mice xenograft model using gefitinib-resistant NSCLC cells [48]. This result strongly supports the potential clinical benefit of a combination treatment of a USP8 inhibitor and TKI.…”

“…However, it is noteworthy that many NSCLC patients who are initially responsive to gefitinib therapy subsequently acquire resistance to gefitinib, owning to secondary mutations in EGFR or amplification of MET gene [48]. RTKs, such as EGFR, ErbB2, ErbB3, and C-Met, have been reported to crosstalk with each other, and one RTK can drive the activity of others.…”