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.

Originele taal-2English
Pagina's (van-tot)2579-2593
Aantal pagina's15
TijdschriftInternational Journal of Cancer
Nummer van het tijdschrift10
Vroegere onlinedatum19 nov 2020
StatusPublished - 15 mei 2021

Bibliografische nota

© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.


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