Mechanisms and management of 3rd‑generation EGFR‑TKI resistance in advanced non‑small cell lung cancer (Review)

Abstract

Targeted therapy with epidermal growth factor receptor (EGFR)‑tyrosine kinase inhibitors (TKIs) is a standard modality of the 1st‑line treatments for patients with advanced EGFR‑mutated non‑small cell lung cancer (NSCLC), and substantially improves their prognosis. However, EGFR T790M mutation is the primary mechanism of 1st‑ and 2nd‑generation EGFR‑TKI resistance. Osimertinib is a representative of the 3rd‑generation EGFR‑TKIs that target T790M mutation, and has satisfactory efficacy in the treatment of T790M‑positive NSCLC with disease progression following use of 1st‑ or 2nd‑generation EGFR‑TKIs. Other 3rd‑generation EGFR‑TKIs, such as abivertinib, rociletinib, nazartinib, olmutinib and alflutinib, are also at various stages of development. However, the occurrence of acquired resistance is inevitable, and the mechanisms of 3rd‑generation EGFR‑TKI resistance are complex and incompletely understood. Genomic studies in tissue and liquid biopsies of resistant patients reveal multiple candidate pathways. The present review summarizes the recent findings in mechanisms of resistance to 3rd‑generation EGFR‑TKIs in advanced NSCLC, and provides possible strategies to overcome this resistance. The mechanisms of acquired resistance mainly include an altered EGFR signaling pathway (EGFR tertiary mutations and amplification), activation of aberrant bypassing pathways (hepatocyte growth factor receptor amplification, human epidermal growth factor receptor 2 amplification and aberrant insulin‑like growth factor 1 receptor activation), downstream pathway activation (RAS/RAF/MEK/ERK and PI3K/AKT/mTOR) and histological/phenotypic transformations (SCLC transformation and epithelial‑mesenchymal transition). The combination of targeted therapies is a promising strategy to treat osimertinib‑resistant patients, and multiple clinical studies on novel combined therapies are ongoing.

Keywords: epidermal growth factor receptor‑tyrosine kinase inhibitor; non‑small cell lung cancer; osimertinib; resistance mechanism; targeted therapy.

Figure 1

Chemical structures of different generations of EGFR-TKIs. Chemical structures were sourced from https://pubchem.ncbi.nlm.nih.gov/. EGFR-TKI, epidermal growth factor receptor-tyrosine kinase inhibitor.

Figure 2

Mechanisms of primary and acquired 3rd-generation EGFR-TKI resistance in advanced EGFR-mutated non-SCLC. BIM, B-cell lymphoma-2 (BCL-2)-like 11; MET, hepatocyte growth factor receptor; HER2, human epidermal growth factor receptor 2; FGFR, fibroblast growth factor receptor; IGF1R, insulin-like growth factors 1 receptor; AXL, anexelekto; SCLC, small cell lung cancer; SCC, squamous cell carcinoma; EGFR-TKI, epidermal growth factor receptor-tyrosine kinase inhibitor.

Figure 3

Mechanisms of acquired 3rd-generation EGFR-TKI resistance in advanced EGFR-mutated non-SCLC. (A) Osimertinib as the 2nd-line treatment. (B) Osimertinib as the 1st-line treatments. (C) Abivertinib. (D) Rociletinib. These pie-charts summarize data from studies that enrolled >15 patients. Different resistant mechanisms might co-exist in the same patient. mut, mutation; amp, amplification; PIK3CA, phosphatidylinositol-3-kinase catalytic α; PTEN, phosphatase and tensin homolog; del, deletion; EGFR-TKI, epidermal growth factor receptor-tyrosine kinase inhibitor; MET, hepatocyte growth factor receptor; HER2, human epidermal growth factor receptor 2; FGFR, fibroblast growth factor receptor; IGF1R, insulin-like growth factors 1 receptor; HGF, hepatocyte growth factor; AXL, anexelekto; SCLC, small cell lung cancer; SCC, squamous cell carcinoma; EGFR-TKI, epidermal growth factor receptor-tyrosine kinase inhibitor; ROS1, c-ros oncogene 1, receptor tyrosine kinase.

Figure 4

Molecular mechanisms of acquired 3rd-generation EGFR-TKI resistance. act, activation; NTRK1, neurotrophic receptor tyrosine kinase 1; ALK, anaplastic lymphocyte kinase; ROS1, c-ros oncogene 1, receptor tyrosine kinase; STAT3, signal transducer and activator of transcription 3; EMT, epithelial-mesenchymal transition; SCLC, small cell lung cancer; SCC, squamous cell carcinoma; MET, hepatocyte growth factor receptor; HER2, human epidermal growth factor receptor 2; FGFR, fibroblast growth factor receptor; IGF1R, insulin-like growth factors 1 receptor; AXL, anexelekto.

Figure 5

Possible overcome strategies to the 3rd-generation EGFR-TKI resistance in advanced EGFR-mutated NSCLC. For patients who developed resistance to the 3rd-generation EGFR-TKI after 1st- or 2nd-line treatment with osimertinib, according to the status of the C797S mutation, different treatment regimens can be adopted. If the C797S and T790M mutations are in the cis structure, a combination of cetuximab with brigatinib or EAI045 is effective, while C797S and T790M mutations in trans are sensitive to a combination of 1st- and 3rd-generation TKIs. For NSCLC with C797S mutation but without T790M mutation, 1st- or 2nd-generation EGFR-TKIs are promising agents. For other heterogeneous resistance mechanisms, combinations of 3rd-generation EGFR-TKIs and other targeted agents, such as MEK inhibitors, MET inhibitors and HER2 inhibitors, are effective treatment options. gen, generation; act, activation; EGFR-TKI, epidermal growth factor receptor tyrosine kinase inhibitor; MET, hepatocyte growth factor receptor; HER2, human epidermal growth factor receptor 2; AXL, anexelekto.