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. Video Abstract.

Keywords: Drug resistance; EGFR; Non-small cell lung cancer; Osimertinib; Targeted therapy.

Fig. 1

Molecular mechanisms of 3rd-generation EGFR-TKI (osimertinib) resistance, including EGFR modification (mutation/amplification), alternative pathway activation (MET/HER2/FGFR1 Amp, IGF1R/AXL Act), downstream pathway activation, epithelial-mesenchymal transition (EMT), histological transition, oncogenes fusions and cell cycle gene aberrations. Once EGFR is activated, it will cause multiple downstream signaling cascades activation such as RAS-RAF-MEK-ERK pathway, PI3K/AKT signal pathway, JAK/STAT signal transduction pathway, thus promoting transcriptional activation, cell proliferation, mitosis, anti-apoptosis, invasion and metastasis. act Activation; amp, amplification, del Deletion, mut Mutation

Fig. 2

Schematic diagram of EGFR molecular domains a Domain of human EGFR and exons encoding it. It locates on chromosome 7, which consists of 28 exons. It consists of an extracellular domain, a hydrophobic transmembrane domain (TM domain), a juxtamembrane domain (JM domain), an intracellular protein tyrosine kinase domain that binds ligands and a C-terminal. b EGFR molecular structure and common EGFR-dependent drug resistance mutation sites, including L858R mutation, T790 M' gatekeeper' mutation and tertiary mutation such as C797S

Fig. 3

Therapeutic strategies based on clinical and vitro studies. Erlotinib combined with osimertinib, or gefitinib combined with osimertinib both have certain effects on the EGFR C797S/T790M trans configuration based on vitro studies and clinical evidence. Brigatinib combined with cetuximab or CH7233163 or BLU-945 treatment exhibited potent anti-tumor activity against the EGFR ex19del /T790M/C797S triple mutation. Brigatinib combined with bevacizumab and osimertinib or EAI045 or BLU-945 combined with cetuximab treatment, have a significant effect on the EGFR L858R-T790M-C797S triple mutation. Afatinib treatment is a potentially effective strategy for EGFR L858R/L718Q/V or EGFR G719S/C or EGFR ex19del/G724S mutation based on clinical cases or research evidence. Gefitinib can combat lung adenocarcinoma with EGFR L858R-cis T790M-L792H triple mutation in vitro

Fig. 4

Evolutionary mechanism of drug resistance and targeted therapeutic strategies. Cell clones with primary EGFR activating mutations (e.g., L858R and ex19del mutation) appeared T790M resistant clones under the selection or induction of the 1st and 2nd generation TKIs. C797S resistant clones appeared under the same mechanism of 3rd generation TKIs. The two mutated genes, C797S and T790M, can be located on the same DNA strand (in cis) or on different DNA strands (in trans). There are now different effective therapeutic strategies for these specific combinations of drug-resistant mutations that have evolved from drug selection