• Lei An, Yueqiang Wang, Guangyao Wu, Zhenxing Wang, Zeyuan Shi, Chang Liu, Chunli Wang, Ming Yi, Chenguang Niu, Shaofeng Duan, Xiaodong Li, Wenxue Tang, Kongming Wu, Shuqing Chen, and Hongen Xu.
• Translational Medicine Center, Huaihe Hospital of Henan University, Henan University, Kaifeng 475000, China.
• Transl Res. 2023 May 1; 255: 142514-25.

AbstractTyrosine kinase inhibitor (TKI) is a standard treatment for patients with NSCLC harboring constitutively active epidermal growth factor receptor (EGFR) mutations. However, most rare EGFR mutations lack treatment regimens except for the well-studied ones. We constructed two EGFR variant libraries containing substitutions, deletions, or insertions using the saturation mutagenesis method. All the variants were located in the EGFR mutation hotspot (exons 18-21). The sensitivity of these variants to afatinib, erlotinib, gefitinib, icotinib, and osimertinib was systematically studied by determining their enrichment in massively parallel cytotoxicity assays using an endogenous EGFR-depleted cell line. A total of 3914 and 70,475 variants were detected in the constructed EGFR Substitution-Deletion (Sub-Del) and exon 20 Insertion (Ins) libraries. Of the 3914 Sub-Del variants, 221 proliferated fast in the control assay and were sensitive to EGFR-TKIs. For the 70,475 Ins variants, insertions at amino acid positions 770-774 were highly enriched in all 5 TKI cytotoxicity assays. Moreover, the top 5% of the enriched insertion variants included a glycine or serine insertion at high frequency. We present a comprehensive reference for the sensitivity of EGFR variants to five commonly used TKIs. The approach used here should be applicable to other genes and targeted drugs.Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

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