PROTAC advantages vs. inhibition... https://www.cell.com/cell-chemical-biology/fulltext/S2451-9456(17)30353-7 The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study Given their well-defined role in human cancers and the broad understanding of their regulation and downstream signaling pathways, we focused our efforts on EGFR, HER2, and c-Met as potential PROTAC targets of interest. Herein, we show effective PROTAC-mediated degradation of these RTKs, including a number of relevant oncogenic mutant isoforms. Our results strongly suggest that not only are RTKs viable substrates for post-translational degradation, but also that the signaling inactivation and growth inhibition achieved by PROTACs is more potent, more sustained, and less susceptible to kinome rewiring than that achieved via RTK inhibition. This provides, to the best of our knowledge, the first evidence of small-molecule-induced internalization of an endogenous RTK and further suggests sorting into endosomes prior to degradation via the proteasome (Figure S4B). Interestingly, preliminary small interfering RNA experiments suggest that this process is clathrin independent (Figure S5E).