Giron Philippe, Eggermont Carolien, Noeparast Amir, Vandenplas Hugo, Teugels Erik, Forsyth Ramses, De Wever Olivier, Aza-Blanc Pedro, Gutierrez Gustavo J, De Grève Jacques
Laboratory of Medical and Molecular Oncology; Oncology Research Center, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium.
Laboratory of Pathophysiological Cell Signaling, Department of Biology, Faculty of Science and Bioengineering Sciences, Vrije Universiteit Brussel, Brussels, Belgium.
Int J Cancer. 2021 May 15;148(10):2579-2593. doi: 10.1002/ijc.33404. Epub 2021 Jan 25.
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.
在非小细胞肺癌（NSCLC）中，表皮生长因子受体（EGFR）的激活突变会诱导对EGFR酪氨酸激酶抑制剂的敏感性。尽管临床反应令人印象深刻，但患者最终仍会复发，因为耐药细胞库持续存在，这最终导致获得性耐药机制。我们进行了一项无偏向的高通量siRNA筛选，以鉴定消除EGFR突变型NSCLC对EGFR靶向治疗反应的蛋白质。去泛素化酶USP13是此次筛选的主要命中靶点。靶向USP13可在体外和体内增加小分子对EGFR抑制的敏感性。USP13通过抵消E3泛素连接酶Cbl家族成员的作用，以一种不依赖肽酶的方式选择性地稳定突变型EGFR。我们得出结论，USP13是一个强大的突变型EGFR特异性共靶点，可提高EGFR靶向治疗的疗效。
