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Distinct co-acquired alterations and genomic evolution during TKI treatment in non-small-cell lung cancer patients with or without acquired T790M mutation

Oncogene volume 39, pages 1846–1859 (2020)Cite this article

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A Correction to this article was published on 12 December 2019

Abstract

EGFR-mutant non-small-cell lung cancer (NSCLC) patients inevitably develop drug resistance when treated with EGFR tyrosine kinase inhibitors (TKIs). Systematic genetic analysis is important to understand drug-resistant mechanisms; however, the clinical significance of co-occurring genetic alterations at baseline, co-acquired mutations at progressive disease (PD), and the clonal evolution remain underinvestigated. We performed targeted sequencing of pre-treatment and PD tumor samples from 54 EGFR-mutant NSCLC patients. Ten additional patients were sequenced using whole-exome sequencing to infer the clonal evolution patterns. We observed a domain-dependent effect of PIK3CA mutation at baseline on patient progression-free survival (PFS). In addition, at baseline, 9q34.3/19p13.3 (NOTCH1/STK11/GNA11) showed a co-deletion pattern, which was associated with a significantly worse PFS (p = 0.00079). T790M-postive patients with other concurrent acquired oncogenic mutations had a significantly shorter PFS (p = 0.005). Besides acquired T790M mutation, chromosomal instability (CIN) related genes, including AURKA and TP53 alterations, were the most frequently acquired events. CIN significantly increased during TKI treatment in T790M-negative patients and is a candidate resistance mechanism to the first-generation TKIs. Clonal evolution analyses suggest that the composition and relationship among resistant subclones, particularly relationship with T790M subclone, affect patients’ outcomes. Overall, our findings of novel co-occurring alterations and clonal evolution patterns can be served as predictive biomarkers to stratify patients and help to better understand the drug-resistant mechanism to TKIs.

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Acknowledgements

Professor Stebbing sits on SABs for Celltrion, Singapore Biotech, Vor Biopharma, TLC Biopharmaceuticals and Benevolent AI, has consulted with Lansdowne partners, Vitruvian and Social Impact Capital and Chairs the Board of Directors for BB Biotech Healthcare Trust and Xerion Healthcare. This study was supported by the National Natural Science Foundation of China (Grant nos. 81702248, 81672972), and Zhejiang Medical and Health Science and Technology Project (Grant nos. 2018KY309, 2017KY239).

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  1. These authors contributed equally: Ying Jin, Hua Bao, Xiuning Le

Authors and Affiliations

  1. Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Hangzhou, Zhejiang, China

    Ying Jin, Xun Shi, Jun Zhao, Guangyuan Lou, Lan Shao, Qiong He, Chen Lin, Yamei Chen, Ming Chen & Xinmin Yu

  2. Department of Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences & Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China

    Ying Jin, Xun Shi, Jun Zhao, Guangyuan Lou, Lan Shao, Qiong He, Chen Lin & Xinmin Yu

  3. Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, Zhejiang, China

    Ying Jin, Yamei Chen & Ming Chen

  4. Translational Medicine Research Centre, Geneseeq Technology Inc., Toronto, ON, Canada

    Hua Bao, Xiaojun Fan, Yang Xu & Xue Wu

  5. Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Xiuning Le, Ming Tang, Kelly Quek, Yasir Y. Elamin, John V. Heymach & Jianjun Zhang

  6. Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, China

    Junrong Yan, Yang W. Shao, Xiaonan Wang & Jiachen He

  7. Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Jianhua Zhang, P. Andrew Futreal & Jianjun Zhang

  8. Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Ignacio I. Wistuba

  9. Department of Surgery and Cancer, Division of Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, W12 0NN, UK

    Justin Stebbing

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  1. Ying Jin
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HB, XF, YX, and XW are the employees of Geneseeq Technology Inc., JY, XW, YWS, and JH are the employees of Nanjing Geneseeq Technology Inc.; JZ reports personal fees from BMS, AstraZeneca, Geneplus, OrigMed, Innovent, grant from Merck, Johnson & Johnson, outside the current work.

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Jin, Y., Bao, H., Le, X. et al. Distinct co-acquired alterations and genomic evolution during TKI treatment in non-small-cell lung cancer patients with or without acquired T790M mutation. Oncogene 39, 1846–1859 (2020). https://doi.org/10.1038/s41388-019-1104-z

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