title: USP8 is a novel target for overcoming gefitinib resistance in lung cancer.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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. 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 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 gefitinib-resistant and -sensitive NSCLC cells.
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.
authors.forename: Sanguine
authors.initials: S
authors.lastname: Byun
authors.forename: Sung-Young
authors.initials: SY
authors.lastname: Lee
authors.forename: Jihoon
authors.initials: J
authors.lastname: Lee
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Jeong
authors.forename: Lee
authors.initials: L
authors.lastname: Farrand
authors.forename: Semi
authors.initials: S
authors.lastname: Lim
authors.forename: Kanamata
authors.initials: K
authors.lastname: Reddy
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Mee-Hyun
authors.initials: MH
authors.lastname: Lee
authors.forename: Hyong Joo
authors.initials: HJ
authors.lastname: Lee
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.forename: Ki
authors.initials: K
authors.lastname: Won Lee
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology; D045744:Cell Line, Tumor; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011480:Protease Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D056827:Endosomal Sorting Complexes Required for Transport; D011480:Protease Inhibitors; D011799:Quinazolines; D020794:Receptor Protein-Tyrosine Kinases; D010450:Endopeptidases; C541534:USP8 protein, human; D043222:Ubiquitin Thiolesterase; D000077156:Gefitinib