EGFR degraders in non‐small‐cell lung cancer: Breakthrough and unresolved issue

Abstract The epidermal growth factor receptor (EGFR) has been well validated as a therapeutic target for anticancer drug discovery. Osimertinib has become the first globally accessible third‐generation EGFR inhibitor, representing one of the most advanced developments in non‐small‐cell lung cancer (NSCLC) therapy. However, a tertiary Cys797 to Ser797 (C797S) point mutation has hampered osimertinib treatment in patients with advanced EGFR‐mutated NSCLC. Several classes of fourth‐generation EGFR inhibitors were consequently discovered with the aim of overcoming the EGFR C797S mutation‐mediated resistance. However, no clinical efficacy data of the fourth‐generation EGFR inhibitors were reported to date, and EGFR C797S mutation‐mediated resistance remains an “unmet clinical need.” Proteolysis‐targeting chimeric molecules (PROTACs) obtained from EGFR‐TKIs have been developed to target drug resistance EGFR in NSCLC. Some PROTACs are from nature products. These degraders compared with EGFR inhibitors showed better efficiency in their cellular potency, inhibition, and toxicity profiles. In this review, we first introduce the structural properties of EGFR, the resistance, and mutations of EGFR, and then mainly focus on the recent advances of EGFR‐targeting degraders along with its advantages and outstanding challenges.