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 EGFRC797S mutation-mediated resistance. However, no clinical efficacy data of the fourth-generation EGFR inhibitors were reported to date, and EGFRC797S 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.
Subject(s)
Acrylamides , Aniline Compounds , Carcinoma, Non-Small-Cell Lung , Indoles , Lung Neoplasms , Pyrimidines , Humans , ErbB Receptors/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic useABSTRACT
OBJECTIVE: Studying forensic medical problem related with RTA leading PTSD and supplying accumulating evidence for psychiatric compensation in court. METHODS: One hundred and fifty six victims of RTA were recruited who applied to court for a costs order. The victims were examined for psychiatric diagnosis by psychiatrists and for rank of impairment by experts in forensic clinical medicine. The self-report psychopathological status and quality of life were also measured. RESULTS: Eighty one victims of 156 (51.92%) fulfilled the criteria for PTSD (ICD-10). Morbidity difference in male and female were significant; The more serious extent of impairment is, the more PTSD'possibility is; The scores in World Health Organization Quality of Life were lower and in SAS and SDS were higher in PTSD group than in non-PTSD group. Acquirement of awarded costs could obviously prevent PTSD. CONCLUSION: The higher PTSD incidence existed in the RTA victims who applied to court for a costs order, and acquirement of awarded costs could obviously prevent PTSD.
