Mutations in the MET tyrosine kinase domain and resistance to tyrosine kinase inhibitors in non-small-cell lung cancer

Respiratory Research

Research

Yu Yao¹  Huaping Yang²  Bo Zhu³  Hui Tian⁴  Yang Xu⁵  Jinfeng Zhang⁵  Junli Zhang⁵  Qiuxiang Ou⁵  Song Wang⁵  Jiaohui Pang⁵  Xiaoying Wu⁵  Zheng Zhao⁶ 

[1] Department of Medical Oncology, First Affiliated Hospital of Xi’an Jiaotong University, 710049, Xi’an, Shaanxi, China;Department of Respiratory Medicine, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China;Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Xi’an Jiaotong University, 710049, Xi’an, Shaanxi, China;Department of Thoracic Surgery, Ningbo Medical Centre Lihuili Hospital, 315046, Ningbo, China;Geneseeq Research Institute, Nanjing Geneseeq Technology Inc., 210000, Nanjing, Jiangsu, China;Shaanxi Cancer Hospital, 309 Yanta West Road, 710000, Xi’an, Shaanxi, China;

关键词: MET;    Tyrosine kinase domain;    NSCLC;    EGFR-TKI;    Genomic profiling;   

DOI  :  10.1186/s12931-023-02329-1

 received in 2022-11-22, accepted in 2023-01-14,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundThe Mesenchymal epithelial transition factor (MET) gene encodes a receptor tyrosine kinase with pleiotropic functions in cancer. MET exon 14 skipping alterations and high-level MET amplification are oncogenic and targetable genetic changes in patients with non-small-cell lung cancer (NSCLC). Resistance to tyrosine kinase inhibitors (TKIs) has been a major challenge for targeted therapies that impairs their clinical efficacies.MethodsEighty-six NSCLC patients were categorized into three cohorts based on the time of detecting MET tyrosine kinase domain (TKD) mutations (cohort 1: at baseline; cohort 2: after MET-TKI treatment; cohort 3: after EGFR-TKI treatment). Baseline and paired TKI treatment samples were analyzed by targeted next-generation sequencing.ResultsMET TKD mutations were highly prevalent in METex14-positive NSCLC patients after MET-TKI treatment, including L1195V, D1228N/H/Y/E, Y1230C/H/N/S, and a double-mutant within codons D1228 and M1229. Missense mutations in MET TKD were also identified at baseline and in post-EGFR-TKI treatment samples, which showed different distribution patterns than those in post-MET-TKI treatment samples. Remarkably, H1094Y and L1195F, absent from MET-TKI-treated patients, were the predominant type of MET TKD mutations in patients after EGFR-TKI treatment. D1228H, which was not found in treatment-naïve patients, also accounted for 14.3% of all MET TKD mutations in EGFR-TKI-treated samples. Two patients with baseline EGFR-sensitizing mutations who acquired MET-V1092I or MET-H1094Y after first-line EGFR-TKI treatment experienced an overall improvement in their clinical symptoms, followed by targeted therapy with MET-TKIs.ConclusionsMET TKD mutations were identified in both baseline and patients treated with TKIs. MET-H1094Y might play an oncogenic role in NSCLC and may confer acquired resistance to EGFR-TKIs. Preliminary data indicates that EGFR-mutated NSCLC patients who acquired MET-V1092I or MET-H1094Y may benefit from combinatorial therapy with EGFR-TKI and MET-TKI, providing insights into personalized medical treatment.

【 授权许可】

CC BY   
© The Author(s) 2023

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