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Targeting USP13 ‐mediated drug tolerance increases the efficacy of EGFR inhibition of mutant EGFR in non‐small cell lung cancer
Author(s) -
Giron Philippe,
Eggermont Carolien,
Noeparast Amir,
Vandenplas Hugo,
Teugels Erik,
Forsyth Ramses,
De Wever Olivier,
AzaBlanc Pedro,
Gutierrez Gustavo J.,
De Grève Jacques
Publication year - 2021
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.33404
Subject(s) - epidermal growth factor receptor , cancer research , mutant , egfr inhibitors , in vivo , ubiquitin , lung cancer , tyrosine kinase , epidermal growth factor , cancer , biology , cell culture , medicine , signal transduction , microbiology and biotechnology , oncology , gene , biochemistry , genetics
In non‐small cell lung cancer (NSCLC), activating mutations in the epidermal growth factor receptor (EGFR) induce sensitivity to EGFR tyrosine kinase inhibitors. Despite impressive clinical responses, patients ultimately relapse as a reservoir of drug‐tolerant cells persist, which ultimately leads to acquired resistance mechanisms. We performed an unbiased high‐throughput siRNA screen to identify proteins that abrogate the response of EGFR‐mutant NSCLC to EGFR‐targeted therapy. The deubiquitinase USP13 was a top hit resulting from this screen. Targeting USP13 increases the sensitivity to EGFR inhibition with small molecules in vitro and in vivo. USP13 selectively stabilizes mutant EGFR in a peptidase‐independent manner by counteracting the action of members of the Cbl family of E3 ubiquitin ligases. We conclude that USP13 is a strong mutant EGFR‐specific cotarget that could improve the treatment efficacy of EGFR‐targeted therapies.