The Lifted Veil of Uncommon EGFR Mutation p.L747P in Non-Small Cell Lung Cancer: Molecular Feature and Targeting Sensitivity to Tyrosine Kinase Inhibitors

Guangjian Yang; Chengming Liu; Jiaqi Hu; Yang Sun; Peizeng Hu; Liu Liu; Haiyan Xu; Dazhou Li; Weihua Li; Yaning Yang; Nan Sun; Jie He; Yan Wang

doi:10.3389/fonc.2022.843299

The Lifted Veil of Uncommon EGFR Mutation p.L747P in Non-Small Cell Lung Cancer: Molecular Feature and Targeting Sensitivity to Tyrosine Kinase Inhibitors

Front Oncol. 2022 Feb 11:12:843299. doi: 10.3389/fonc.2022.843299. eCollection 2022.

Authors

Guangjian Yang¹, Chengming Liu², Jiaqi Hu³, Yang Sun³, Peizeng Hu⁴, Liu Liu³, Haiyan Xu⁵, Dazhou Li⁶, Weihua Li⁷, Yaning Yang¹, Nan Sun², Jie He², Yan Wang¹

Affiliations

¹ Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
² Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
³ Drug Discovery Business Unit, PharmaBlock Sciences (Nanjing), Inc., Nanjing, China.
⁴ Department of Traditional Chinese Medicine, Yidu Central Hospital of Weifang, Qingzhou, China.
⁵ Department of Comprehensive Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
⁶ College of Computer Science and Technology, Shenyang University of Chemical Technology, Shenyang, China.
⁷ Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Abstract

Objectives: The uncommon p.L747P mutation in epidermal growth factor receptor (EGFR) exon 19 reveals to alter the response to tyrosine kinase inhibitors (TKIs) in patients diagnosed with advanced non-small cell lung cancer (NSCLC). However, the underlying mechanism is still not clear. This study aimed to investigate the clinical outcomes, binding affinities, and modes of action of currently available EGFR TKIs towards p.L747P mutation.

Materials and methods: Clinical data of NSCLC patients harboring p.L747P mutation who had received different generations of EGFR TKIs were collected from medical records. Computational structure of p.L747P was constructed and in vitro cellular kinase inhibition assay and mice xenograft experiment were performed to predict and confirm the binding affinities and antitumor activities of diverse EGFR TKIs.

Results: A total of five metastatic NSCLC patients with p.L747P mutation were included in the final analysis. Patients treated with second-generation (2G) TKI afatinib achieved numerically longer progression-free survival (range 2.4-8.5 months) than that with first-generation (1G, range 1.4-5.5 months) or third-generation (3G, range 1.6-7.5 months) TKIs. None of the patients administered 1G or 3G TKIs achieved tumor response, but two-thirds of them treated with afatinib achieved partial response. Dynamics simulation predicted that 2G TKIs presented the best binding affinity to p.L747P mutation. The cellular kinase inhibition assay and mice xenograft experiment confirmed that afatinib could potently inhibit p.L747P-mutant cells and significantly reduce p.L747P-mutant tumor growth (P< 0.001), together with reduced phosphorylation of EGFR and its downstream signalings.

Conclusions: The uncommon p.L747P mutation in EGFR exon 19 resulted in a poor response to first-generation EGFR TKIs. Afatinib revealed a better clinical response and binding affinity compared with osimertinib for this specific alteration.

Keywords: EGFR; molecular feature; non-small cell lung cancer; p.L747P mutation; targeting sensitivity; tyrosine kinase inhibitor.