Wolf Gernot, Craigon Conner, Teoh Shao Thing, Essletzbichler Patrick, Onstein Svenja, Cassidy Diane, Uijttewaal Esther C H, Dvorak Vojtech, Cao Yuting, Bensimon Ariel, Elling Ulrich, Ciulli Alessio, Superti-Furga Giulio
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
Centre for Targeted Protein Degradation, School of Life Sciences, University of Dundee, 1 James Lindsay Place, Dundee DD1 5JJ, UK.
Cell Chem Biol. 2025 Feb 20;32(2):291-306.e6. doi: 10.1016/j.chembiol.2024.11.009. Epub 2025 Jan 3.
Proteolysis targeting chimeras (PROTACs) are bifunctional molecules that induce selective protein degradation by linking an E3 ubiquitin ligase enzyme to a target protein. This approach allows scope for targeting "undruggable" proteins, and several PROTACs have reached the stage of clinical candidates. However, the roles of cellular transmembrane transporters in PROTAC uptake and efflux remain underexplored. Here, we utilized transporter-focused genetic screens to identify the ATP-binding cassette transporter ABCC1/MRP1 as a key PROTAC resistance factor. Unlike the previously identified inducible PROTAC exporter ABCB1/MDR1, ABCC1 is highly expressed among cancers of various origins and constitutively restricts PROTAC bioavailability. Moreover, in a genome-wide PROTAC resistance screen, we identified candidates involved in processes such as ubiquitination, mTOR signaling, and apoptosis as genetic factors involved in PROTAC resistance. In summary, our findings reveal ABCC1 as a crucial constitutively active efflux pump limiting PROTAC efficacy in various cancer cells, offering insights for overcoming drug resistance.
蛋白酶靶向嵌合体（PROTACs）是一种双功能分子，通过将E3泛素连接酶与靶蛋白相连来诱导选择性蛋白质降解。这种方法为靶向“不可成药”的蛋白质提供了空间，并且几种PROTACs已进入临床候选阶段。然而，细胞跨膜转运蛋白在PROTAC摄取和外排中的作用仍未得到充分研究。在这里，我们利用聚焦转运蛋白的基因筛选来确定ATP结合盒转运蛋白ABCC1/MRP1是关键的PROTAC耐药因子。与先前鉴定的可诱导PROTAC外排转运蛋白ABCB1/MDR1不同，ABCC1在各种起源的癌症中高度表达，并持续限制PROTAC的生物利用度。此外，在全基因组PROTAC耐药筛选中，我们确定了参与泛素化、mTOR信号传导和凋亡等过程的候选基因作为与PROTAC耐药相关的遗传因素。总之，我们的研究结果揭示ABCC1是一种关键的组成型活性外排泵，限制了PROTAC在各种癌细胞中的疗效，为克服耐药性提供了见解。
