Targeted Strategies for Degradation of Key Transmembrane Proteins in Cancer.

Targeted protein degradation is an attractive technology for cancer treatment due to its ability to overcome the unpredictability of the small molecule inhibitors that cause resistance mutations. In recent years, various targeted protein degradation strategies have been developed based on the ubiquitin-proteasome system in the cytoplasm or the autophagy-lysosomal system during endocytosis. In this review, we describe and compare technologies for the targeted inhibition and targeted degradation of the epidermal growth factor receptor (EGFR), one of the major proteins responsible for the onset and progression of many types of cancer.

Targeting Degradation of EGFR through the Allosteric Site Leads to Cancer Cell Detachment-Promoted Death.

Targeting epidermal growth factor receptor (EGFR) with tyrosine kinase inhibitors (TKI) has been widely exploited to disrupt aberrant phosphorylation flux in cancer. However, a bottleneck of potent TKIs is the acquisition of drug resistance mutations, secondary effects, and low ability to attenuate tumor progression. We have developed an alternative means of targeting EGFR that relies on protein degradation through two consecutive routes, ultimately leading to cancer cell detachment-related death.