Drug resistance mechanisms and progress in the treatment of EGFR‑mutated lung adenocarcinoma (Review)

Abstract

According to global cancer data, lung cancer was the leading cause of cancer-related death in 2020. With the diversification of treatment strategies, the survival outcomes of patients with advanced lung cancer have improved significantly, but the 5-year overall survival rate remains <20%. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the preferred treatment for lung adenocarcinoma patients with EGFR-sensitive mutations; however, acquired drug resistance is inevitable. Osimertinib (a third-generation EGFR inhibitor) is the most commonly used drug for cancers with a secondary T790M mutation. Unfortunately, acquired drug resistance against third-generation drugs still emerges. The C797s mutation is the primary acquired resistance mechanism against Osimertinib. Research on fourth-generation EGFR-TKI drugs with a C797s mutation is currently at various experimental stages, and no drug has been approved for clinical use. In addition to the resistance mechanisms described above, HER2 amplification, MET amplification, PIK3A mutation, KRAS mutation, BRAF mutation, transformation to small cell lung cancer, transformation to lung squamous cell carcinoma, and EMT have been reported as mechanisms of acquired drug resistance to first-, second-and third-generation EGFR-TKIs. These mechanisms are noted in a relatively high proportion of tumors, but treatment options are limited. In recent years, immunotherapy has made progress in the treatment of several cancers, including advanced EGFR-mutated non-small cell lung cancer (NSCLC). Due to the relatively high frequency of EGFR mutation in patients with lung adenocarcinoma in China, an increased number of patients develop EGFR-TKI resistance, and subsequent treatment options are critical. This article reviews the mechanisms of drug resistance to different EGFR-TKIs and treatment progression, providing ideas for the follow-up treatment for EGFR-resistant patients.

Regulation of Autophagy via Carbohydrate and Lipid Metabolism in Cancer

“…Genetic factors are also important. The most common genetic risk factors are mutations in EGFR (epidermal growth factor receptors) and ALK (anaplastic lymphoma kinase) [ 304 , 305 ]. EGFR mutations are more common in Asian populations [ 306 ].…”

Regulation of Autophagy via Carbohydrate and Lipid Metabolism in Cancer

“…HIV and HPV infection may also increase the risk of developing lung cancer, although it is unclear if this observation is being driven predominantly by smoking exposures [304][305][306][307] Genetic factors are also important. The most common genetic risk factors are mutations in EGFR (epidermal growth factor receptors) and ALK (anaplastic lymphoma kinase) [308][309]. EGFR mutations are more common in Asian populations [310].…”

Efficacy of Definitive Radiotherapy for Patients with Clinical Stage IIIB or IIIC Lung Adenocarcinoma and Epidermal Growth Factor Receptor (EGFR) Mutations Treated Using First- or Second-Generation EGFR Tyrosine Kinase Inhibitors

“…Currently available EGFR TKIs can be classified as first (e.g., gefitinib or erlotinib), second (e.g., afatinib or dacomitinib), and third (e.g., osimertinib) generation [ 6 ]. A comprehensive National Health Insurance (NHI) system has been implemented in Taiwan since 1995.…”