Cellular Resistance Mechanisms to Targeted Protein Degradation Converge Toward Impairment of the Engaged Ubiquitin Transfer Pathway

• DOI: 10.1021/acschembio.9b00525
• Publication Date: 2019-09-25T19:29:03Z
• Authors: Philipp Ottis; Chiara Palladino; Phillip Thienger; Adrian Britschgi; Christian Heichinger; Marco Berrera; Alice Julien-Lafe...; Filip Roudnicky; Tony Kam-Thong; James R. Bischoff; Bruno Martoglio; Piergiorgio Petta...
• Keywords: Cereblon; Degron; Ubiquitin-Protein Ligases; BRD4; Protein Degradation; Deubiquitinating enzyme; Proteotoxicity

Proteolysis targeting chimeras are bifunctional small molecules capable of recruiting a target protein interest to an E3 ubiquitin ligase that facilitates ubiquitination followed by proteasome-mediated degradation. The first acting on this novel therapeutic paradigm have just entered clinical testing. Here, using Bromodomain Containing 4 (BRD4) degraders engaging cereblon and Von Hippel-Lindau ligases, we investigated key determinants resistance new mode action. A loss-of-function screen for genes required BRD4 degradation revealed strong dependence the E2 ligases as well members COP9 signalosome complex both cereblon- Hippel–Lindau-engaging degraders. Cancer cell lines raised resist manifested degrader-specific mechanism resistance, resulting from loss components proteasome system. In addition, degrader profiling in cancer line panel differential pattern activity Hippel–Lindau- cereblon-based degraders, highlighting need identification degradation-predictive biomarkers enabling effective patient stratification.