Toward the next generation EGFR inhibitors: an overview of osimertinib resistance mediated by EGFR mutations in non-small cell lung cancer

Abstract

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is currently the standard first-line therapy for EGFR-mutated advanced non-small cell lung cancer (NSCLC). The life quality and survival of this subgroup of patients were constantly improving owing to the continuous iteration and optimization of EGFR-TKI. Osimertinib, an oral, third-generation, irreversible EGFR-TKI, was initially approved for the treatment of NSCLC patients carrying EGFR T790M mutations, and has currently become the dominant first-line targeted therapy for most EGFR mutant lung cancer. Unfortunately, resistance to osimertinib inevitably develops during the treatment and therefore limits its long-term effectiveness. For both fundamental and clinical researchers, it stands for a major challenge to reveal the mechanism, and a dire need to develop novel therapeutics to overcome the resistance. In this article, we focus on the acquired resistance to osimertinib caused by EGFR mutations which account for approximately 1/3 of all reported resistance mechanisms. We also review the proposed therapeutic strategies for each type of mutation conferring resistance to osimertinib and give an outlook to the development of the next generation EGFR inhibitors.

A graphSAGE discovers synergistic combinations of Gefitinib, paclitaxel, and Icotinib for Lung adenocarcinoma management by targeting human genes and proteins: the RAIN protocol

“…There is a requirement for new therapeutic advancements for patients with EGFR-mutant NSCLC and liver metastases. [145][146][147][148][149][150][151][152] Crizotinib, a small molecule tyrosine kinase inhibitor, specifically addresses aberrant proteins in cancerous cells. Employed as an initial treatment, it is utilized in the management of non-small cell lung carcinoma (NSCLC) that meets certain genetic mutation criteria.…”

The Resistance to EGFR-TKIs in Non-Small Cell Lung Cancer: From Molecular Mechanisms to Clinical Application of New Therapeutic Strategies

“…Rare point EGFR mutations in exon 20 have been also identified in the C796 residue such as the G796R (0.56% of patients with lung adenocarcinoma treated with osimertinib), G796S, and G796D mutations, which are adjacent to C797 in exon 20 and can sterically impair the binding of osimertinib to EGFR [ 103 , 107 , 108 , 109 ].…”

Anti-cancer effects of bis-oxidized thiopyran derivatives on non-small cell lung cancer: rational design, synthesis, and activity evaluation

“…22–24 The problem of resistance to the previous EGFR-TKIs in advanced NSCLC patients with EGFR gene-sensitive mutations is solved, and adverse reactions are reduced. 25,26 Osimertinib ( AZD9291 ) is a third-generation EGFR-TKI developed by AstraZeneca in 2015 and has been quickly used in the first-line treatment of NSCLC due to its efficacy and low toxicity in patients with advanced NSCLC. 27–30 It is a highly bioavailable third-generation irreversible inhibitor with strong therapeutic effects against EGFR L858R and EGFR T790M and low affinity for the wild-type EGFR.…”