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Targeting USP13 U+2010mediated drug tolerance increases the efficacy of EGFR inhibition of mutant EGFR in nonU+2010small cell lung cancer

Tijdschriftbijdrage - Tijdschriftartikel

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.
Tijdschrift: International Journal of Cancer
ISSN: 0020-7136
Issue: 10
Volume: 148
Pagina's: 2579 - 2593
Jaar van publicatie:2021