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ORIGINAL RESEARCH article

Front. Oncol.
Sec. Thoracic Oncology
Volume 14 - 2024 | doi: 10.3389/fonc.2024.1470827

The potential role of next-generation sequencing in identifying MET amplification and disclosing resistance mechanisms in NSCLC patients with osimertinib resistance

Provisionally accepted
Xiao Xiao Xiao Xiao 1*Ren Xu Ren Xu 1*Jun Lu Jun Lu 2Beibei Xin Beibei Xin 3*Chenyang Wang Chenyang Wang 3*Kexin Zhu Kexin Zhu 3*Hao Zhang Hao Zhang 1*Xinyu Chen Xinyu Chen 1*
  • 1 Changchun University of Science and Technology, Changchun, China
  • 2 Shanghai Chest Hospital, Shanghai, China
  • 3 Shanghai Rightongene Biotechnology Co., Ltd., Shanghai, China

The final, formatted version of the article will be published soon.

    Purposes: Osimertinib, one of the third-generation EGFR-tyrosine kinase inhibitors (TKIs) designed to target EGFR T790M mutation, significantly improves the prognosis of lung cancer. However, drug resistance still happens and MET amplification is responsible for one of the main causes. Fluorescence in situ hybridization (FISH) is the gold standard for MET amplification detection, but fundamentally limited by observer subjectivity. Herein, we assessed the value of next-generation sequencing (NGS) method in MET amplification detection in non-small cell lung cancer (NSCLC), as well as revealed the mutation profiling of NSCLC patients with osimertinib resistance to provide some valuable clues to the mechanisms of resistance. Methods: A total of 317 cancer tissue samples from 317 NSCLC patients at time of progression following osimertinib were submitted to NGS and only 96 tissues were tested by FISH simultaneously. With FISH results as gold standard, enumeration algorithm was applied to establish the optimal model for identifying MET amplification using gene copy number (GCN) data. Results: The optimal model for identifying MET amplification was constructed based on the GCN of MET, BRAF, CDK6 and CYP3A4, which achieved a 74.0% overall agreement with FISH and performed well in identifying MET amplification except polysomy with a sensitivity of 85.7% and a specificity of 93.9%. The inconsistency between NGS and FISH occurred mainly in polysomy subtype, while MET GCN ≥ 5 could be reliably recognized by NGS. Moreover, the most frequently mutated genes in NSCLC patients with osimertinib resistance were EGFR (59.94%), followed by TP53 (43.85%), NRG1 (9.46%), PIK3CA (6.31%), and ATM (5.36%). The known resistance mechanisms, including MET amplification, EGFR (C797S, L718Q/R), TP53, CDK4, CDK6, CDKN2A, BRAF, KRAS, NRAS and PIK3CA mutations were also disclosed in our cohort. Conclusions: NGS assay can achieve a high concordance with FISH in MET amplification detection and has advantages in portraying various genetic alterations, which is of worthy in clinical promotion.

    Keywords: Next-generation sequencing (NGS) next generation sequencing, Non-small cell lung cancer, MET amplification, Osimertinib resistance, fish

    Received: 26 Jul 2024; Accepted: 07 Oct 2024.

    Copyright: © 2024 Xiao, Xu, Lu, Xin, Wang, Zhu, Zhang and Chen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Xiao Xiao, Changchun University of Science and Technology, Changchun, China
    Ren Xu, Changchun University of Science and Technology, Changchun, China
    Beibei Xin, Shanghai Rightongene Biotechnology Co., Ltd., Shanghai, China
    Chenyang Wang, Shanghai Rightongene Biotechnology Co., Ltd., Shanghai, China
    Kexin Zhu, Shanghai Rightongene Biotechnology Co., Ltd., Shanghai, China
    Hao Zhang, Changchun University of Science and Technology, Changchun, China
    Xinyu Chen, Changchun University of Science and Technology, Changchun, China

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