Lysosome‐targeting chimera (LYTAC): A silver bullet for targeted degradation of oncogenic membrane proteins

Activation of EGFR signaling promotes cell proliferation, survival, angiogenesis and metastasis of diverse malignancies. [...]hepatocyte growth factor receptor (c-Met, HGFR) is another oncogenic receptor tyrosine kinase in diverse cancers. [...]severe acquired resistance (e.g., via EGFR mutations) and limited therapeutic efficacy (slightly prolonged overall survival) of these treatments restrict their clinical benefit for patients. [...]nonenzymatic function of membrane proteins, such as protein–protein interactions, could not be interfered with by kinase inhibitors or monoclonal antibodies, calling for new strategies to control these oncogenic membrane proteins. The results indicated that inhibiting retromer genes (e.g., VPS35, SNX3, VPS29, and VPS26A) to reduce LYTAC recycling enhanced the target degradation. [...]genes that involved in cullin3 (CUL3) neddylation, such as CUL3, UBA3, and CAND1, promoted the E3 ligase activity as well as the transport of LYTAC-target protein complexes to lysosomes.