USP8 is a novel target for overcoming gefitinib resistance in lung cancer

Sanguine Byun, Sung Young Lee, Jihoon Lee, Chul Ho Jeong, Lee Farrand, Semi Lim, Kanamata Reddy, Ji Young Kim, Mee Hyun Lee, Hyong Joo Lee, Ann M. Bode, Ki Won Lee, Zigang Dong

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61 Citations (Scopus)

Abstract

Purpose: Common treatment modalities for non-small cell lung cancer (NSCLC) involve the EGF 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 downregulation of several receptor tyrosine kinases (RTK) including EGFR, ERBB2, ERBB3, and MET.Wealso determined that a synthetic USP8 inhibitor markedly decreased the viability of gefitinib-resistant and -sensitiveNSCLC 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 show 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 gefitinibresistant and -sensitive NSCLC cells.

Original languageEnglish
Pages (from-to)3894-3904
Number of pages11
JournalClinical Cancer Research
Volume19
Issue number14
DOIs
Publication statusPublished - 2013 Jul 15

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Byun, S., Lee, S. Y., Lee, J., Jeong, C. H., Farrand, L., Lim, S., Reddy, K., Kim, J. Y., Lee, M. H., Lee, H. J., Bode, A. M., Lee, K. W., & Dong, Z. (2013). USP8 is a novel target for overcoming gefitinib resistance in lung cancer. Clinical Cancer Research, 19(14), 3894-3904. https://doi.org/10.1158/1078-0432.CCR-12-3696