Acquired Resistance Mechanism of EGFR Kinase Domain Duplication to EGFR TKIs in Non–Small Cell Lung Cancer
1
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Purpose: Epidermal growth factor receptor kinase domain duplication (EGFR-KDD) is a rare and poorly understood oncogenic mutation in non-small cell lung cancer (NSCLC). We aimed to investigate the acquired resistance mechanism of EGFR-KDD against EGFR-TKIs. Materials and methods: We identified EGFR-KDD in tumor tissue obtained from a patient with stage IV lung adenocarcinoma and established the patient-derived cell line SNU-4784. We also established several EGFR-KDD Ba/F3 cell lines: EGFR-KDD wild type (EGFR-KDDWT), EGFR-KDD domain 1 T790M (EGFR-KDDD1T), EGFR-KDD domain 2 T790M (EGFR-KDDD2T), and EGFR-KDD both domain T790M (EGFR-KDDBDT). We treated the cells with EGFR tyrosine kinase inhibitors (TKIs) and performed cell viability assays, immunoblot assays, and ENU (N-ethyl-N-nitrosourea) mutagenesis screening. Results: In cell viability assays, SNU-4784 cells and EGFR-KDDWT Ba/F3 cells were sensitive to 2nd generation and 3rd generation EGFR TKIs. In contrast, the T790M-positive EGFR-KDD Ba/F3 cell lines (EGFR-KDDT790M) were only sensitive to 3rd generation EGFR TKIs. In ENU mutagenesis screening, we identified the C797S mutation in kinase domain 2 of EGFR-KDDBDT Ba/F3 cells. Based on this finding, we established an EGFR-KDD domain 1 T790M/domain 2 cis-T790M+C797S (EGFR-KDDT/T+C) Ba/F3 model, which was resistant to EGFR TKIs and anti-EGFR monoclonal antibody combined with EGFR TKIs. Conclusion: Our study reveals that the T790M mutation in EGFR-KDD confers resistance to 1st and 2nd generation EGFR TKIs, but is sensitive to 3rd generation EGFR TKIs. In addition, we identified that the C797S mutation in kinase domain 2 of EGFR-KDDT790M mediates a resistance mechanism against 3rd generation EGFR TKIs.
Abstract
Purpose: Epidermal growth factor receptor kinase domain duplication (EGFR-KDD) is a rare and poorly understood oncogenic mutation in non-small cell lung cancer (NSCLC). We aimed to investigate the acquired resistance mechanism of EGFR-KDD against EGFR-TKIs. Materials and methods: We identified EGFR-KDD in tumor tissue obtained from a patient with stage IV lung adenocarcinoma and established the patient-derived cell line SNU-4784. We also established several EGFR-KDD Ba/F3 cell lines: EGFR-KDD wild type (EGFR-KDDWT), EGFR-KDD domain 1 T790M (EGFR-KDDD1T), EGFR-KDD domain 2 T790M (EGFR-KDDD2T), and EGFR-KDD both domain T790M (EGFR-KDDBDT). We treated the cells with EGFR tyrosine kinase inhibitors (TKIs) and performed cell viability assays, immunoblot assays, and ENU (N-ethyl-N-nitrosourea) mutagenesis screening. Results: In cell viability assays, SNU-4784 cells and EGFR-KDDWT Ba/F3 cells were sensitive to 2nd generation and 3rd generation EGFR TKIs. In contrast, the T790M-positive EGFR-KDD Ba/F3 cell lines (EGFR-KDDT790M) were only sensitive to 3rd generation EGFR TKIs. In ENU mutagenesis screening, we identified the C797S mutation in kinase domain 2 of EGFR-KDDBDT Ba/F3 cells. Based on this finding, we established an EGFR-KDD domain 1 T790M/domain 2 cis-T790M+C797S (EGFR-KDDT/T+C) Ba/F3 model, which was resistant to EGFR TKIs and anti-EGFR monoclonal antibody combined with EGFR TKIs. Conclusion: Our study reveals that the T790M mutation in EGFR-KDD confers resistance to 1st and 2nd generation EGFR TKIs, but is sensitive to 3rd generation EGFR TKIs. In addition, we identified that the C797S mutation in kinase domain 2 of EGFR-KDDT790M mediates a resistance mechanism against 3rd generation EGFR TKIs.
참고문헌 (29)
- Herbst RS, "The biology and management of non-small cell lung cancer", Nature, 553, pp.446~454 (2018)
- Lynch TJ, "Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib", N Engl J Med, 350, pp.2129~2139 (2004)
- Paez JG, "EGFR mutations in lung cancer : correlation with clinical response to gefitinib therapy", Science, 304, pp.1497~1500 (2004)
- Seo JS, "The transcriptional landscape and mutational profile of lung adenocarcinoma", Genome Res, 22, pp.2109~2119 (2012)
- Gazdar AF, "Activating and resistance mutations of EGFR in non-small-cell lung cancer : role in clinical response to EGFR tyrosine kinase inhibitors", Oncogene, 28(Suppl 1), pp.S24~S31 (2009)
- Costa DB, "Kinase inhibitor-responsive genotypes in EGFR mutated lung adenocarcinomas : moving past common point mutations or indels into uncommon kinase domain duplications and rearrangements", Transl Lung Cancer Res, 5, pp.331~337 (2016)
- Du Z, "Mechanisms of receptor tyrosine kinase activation in cancer", Mol Cancer, 17, pp.58~ (2018)
- Gallant JN, "EGFR kinase domain duplication(EGFR-KDD)is a novel oncogenic driver in lung cancer that is clinically responsive to afatinib", Cancer Discov, 5, pp.1155~1163 (2015)
- Du Z, "Structure-function analysis of oncogenic EGFR Kinase Domain Duplication reveals insights into activation and a potential approach for therapeutic targeting", Nat Commun, 12, pp.1382~ (2021)
- Zhu YC, "Lung adenocarcinoma patient with an EGFR kinase domain duplication(KDD)and the response to icotinib", J Thorac Dis, 10, pp.E359~E363 (2018)
- Oxnard GR, "Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer : distinct natural history of patients with tumors harboring the T790M mutation", Clin Cancer Res, 17, pp.1616~1622 (2011)
- Yu HA, "Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers", Clin Cancer Res, 19, pp.2240~2247 (2013)
- Sequist LV, "Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors", Sci Transl Med, 3, pp.75~ (2011)[DOI]
- Sun‑Wha Im, "A newly developed capture-based sequencing panel for genomic assay of lung cancer", Genes & Genomics, 42(7), pp.751~759 (2020), 한국유전학회[DOI]
- Kim TM, "Mechanisms of acquired resistance to AZD9291 : a mutation-selective, irreversible EGFR inhibitor", J Thorac Oncol, 10, pp.1736~1744 (2015)
- Lee Y, "Preclinical modeling of osimertinib for NSCLC with EGFR exon 20 insertion mutations", J Thorac Oncol, 14, pp.1556~1566 (2019)
- Normanno N, "Epidermal growth factor receptor(EGFR)signaling in cancer", Gene, 366, pp.2~16 (2006)
- Ahn MJ, "Lazertinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer : results from the dose escalation and dose expansion parts of a first-in-human, open-label, multicentre, phase 1-2 study", Lancet Oncol, 20, pp.1681~1690 (2019)
- Jia Y, "Overcoming EGFR(T790M)and EGFR(C797S)resistance with mutant-selective allosteric inhibitors", Nature, 534, pp.129~132 (2016)
- Uchibori K, "Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non-small-cell lung cancer", Nat Commun, 8, pp.14768~ (2017)
- Ozer BH, "Activity and cellular localization of an oncogenic glioblastoma multiforme-associated EGF receptor mutant possessing a duplicated kinase domain", Oncogene, 29, pp.855~864 (2010)
- Baik CS, "Durable response to tyrosine kinase inhibitor therapy in a lung cancer patient harboring epidermal growth factor receptor tandem kinase domain duplication", J Thorac Oncol, 10, pp.e97~e99 (2015)
- Garassino MC, "Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours(TAILOR) : a randomised controlled trial", Lancet Oncol, 14, pp.981~988 (2013)
- Kawaguchi T, "Randomized phase III trial of erlotinib versus docetaxel as second-or third-line therapy in patients with advanced non-small-cell lung cancer : Docetaxel and Erlotinib Lung Cancer Trial(DELTA)", J Clin Oncol, 32, pp.1902~1908 (2014)
- Wang J, "Clinical outcomes of EGFR kinase domain duplication to targeted therapies in NSCLC", Int J Cancer, 144, pp.2677~2682 (2019)
- Kim JT, "Patient with stage IV NSCLC and CNS metastasis with EGFR exon 18-25 kinase domain duplication with response to osimertinib as a first-line therapy", JCO Precision Oncol, 5, pp.88~92 (2021)
- Thress KS, "Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M", Nat Med, 21, pp.560~562 (2015)
- Niederst MJ, "The allelic context of the C797S mutation acquired upon treatment with third-generation EGFR inhibitors impacts sensitivity to subsequent treatment strategies", Clin Cancer Res, 21, pp.3924~3933 (2015)
- 박세훈, "EGFR C797S as a Resistance Mechanism of Lazertinib in Non-small Cell Lung Cancer with EGFR T790M Mutation", Cancer Research and Treatment, 52(4), pp.1288~1290 (2020), 대한암학회[DOI]