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Uncommon frame-shift exon 19 EGFR mutations are sensitive to EGFR tyrosine kinase inhibitors in non-small cell lung carcinoma

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Abstract

Exons 19–21 EGFR activating mutations are predictive biomarkers of response to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). However, uncommon exon 19 EGFR mutations, due to their low frequency, have an uncertain biological and clinical significance and very little is known about their TKI sensitivity. This study was designed to describe the TKI sensitivity of a small cohort of lung adenocarcinomas bearing uncommon exon 19 mutations and to evaluate in silico the correlation between frame-shift exon 19 mutations and EGFR sequence/structure modification. Among 1168 NSCLCs screened for EGFR mutational status in our Institutions between 2011 and 2016, seven uncommon exon 19 EGFR mutations were further evaluated: five complex mutations, characterized by a deletion followed by a single-nucleotide insertion, a macrodeletion of 25 bp, and a 19 bp duplication. Interestingly, three patients harboring frame-shift mutations (i.e., one complex mutation, the macrodeletion, and the duplication) showed disease stability and considerably long PFS and OS upon TKI therapy. By contrast, three patients with in-frame complex deletions, independently of the mutation starting point, showed poor/lack of response to TKI therapy. In silico structural analysis showed that sensitivity to TKIs correlates with structural changes in the length and conformation of EGFR C-helix in frame-shift mutations. These data suggest that not all uncommon exon 19 EGFR mutations have the same TKI sensitivity and that frame-shift mutations are responsive to TKIs therapy.

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References

  1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ. Cancer statistics, 2008. CA Cancer J Clin. 2008. https://doi.org/10.3322/CA.2007.0010.

    Google Scholar 

  2. Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 2008. https://doi.org/10.4065/83.5.584.

    Google Scholar 

  3. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129–39.

    Article  CAS  PubMed  Google Scholar 

  4. Sordella R, Bell DW, Haber DA, Settleman J. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science. 2004;305:1163–7.

    Article  CAS  PubMed  Google Scholar 

  5. Paez JG, Jänne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497–500.

    Article  CAS  PubMed  Google Scholar 

  6. Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, Singh B, Heelan R, Rusch V, Fulton L, Mardis E, Kupfer D, Wilson R, Kris M, Varmus H. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA. 2004;101:13306–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci USA. 1977;74:5463–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. DeLano MC, Cao Y. High b-value diffusion imaging. Neuroimaging Clin N Am. 2002;12:21–34.

    Article  PubMed  Google Scholar 

  9. Jorissen RN, Walker F, Pouliot N, Garrett TP, Ward CW, Burgess AW. Epidermal growth factor receptor: mechanisms of activation and signalling. Exp Cell Res. 2003;284:31–53.

    Article  CAS  PubMed  Google Scholar 

  10. Kumar A, Petri ET, Halmos B, Boggon TJ. Structure and clinical relevance of the epidermal growth factor receptor in human cancer. J Clin Oncol. 2008. https://doi.org/10.1200/JCO.2007.12.1178.

    Google Scholar 

  11. Politi K, Lynch TJ. Two sides of the same coin: EGFR exon 19 deletions and insertions in lung cancer. Clin Cancer Res. 2012;18:1490–2. https://doi.org/10.1158/1078-0432.CCR-11-3282.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gazdar AF, Shigematsu H, Herz J, Minna JD. Mutations and addiction to EGFR: the Achilles ‘heal’ of lung cancers? Trends Mol Med. 2004;10:481–6.

    Article  CAS  PubMed  Google Scholar 

  13. Zhang Z, Stiegler AL, Boggon TJ, Kobayashi S, Halmos B. EGFR-mutated lung cancer: a paradigm of molecular oncology. Oncotarget. 2010;1:497–514.

    PubMed  PubMed Central  Google Scholar 

  14. He M, Capelletti M, Nafa K, Yun CH, Arcila ME, Miller VA, et al. EGFR exon 19 insertions: a new family of sensitizing EGFR mutations in lung adenocarcinoma. Clin Cancer Res. 2012;18:1790–7.

    Article  CAS  PubMed  Google Scholar 

  15. Otto C, Csanadi A, Fisch P, Werner M, Kayser G. Molecular modeling and description of a newly characterized activating mutation of the EGFR gene in non-small cell lung cancer. Diagn Pathol. 2012. https://doi.org/10.1186/1746-1596-7-146.

    PubMed  PubMed Central  Google Scholar 

  16. Lee VH, Tin VP, Choy TS, Lam KO, Choi CW, Chung LP, et al. Association of exon 19 and 21 EGFR mutation patterns with treatment outcome after first-line tyrosine kinase inhibitor in metastatic non-small-cell lung cancer. J Thorac Oncol. 2013. https://doi.org/10.1097/JTO.0b013e31829f684a.

    Google Scholar 

  17. Han SW, Kim TY, Hwang PG, Jeong S, Kim J, Choi IS, et al. Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol. 2005;23:2493–501.

    Article  CAS  PubMed  Google Scholar 

  18. Wu JY, Yu CJ, Chang YC, Yang CH, Shih JY, Yang PC. Effectiveness of tyrosine kinase inhibitors on “uncommon” epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer. Clin Cancer Res. 2011;17:3812–21.

    Article  CAS  PubMed  Google Scholar 

  19. Yu G, Xie X, Sun D, Geng J, Fu F, Zhang L, et al. EGFR mutation L747P led to gefitinib resistance and accelerated liver metastases in a Chinese patient with lung adenocarcinoma. Int J Clin Exp Pathol. 2015;8:8603–6.

    PubMed  PubMed Central  Google Scholar 

  20. Wu SG, Gow CH, Yu CJ, Chang YL, Yang CH, Hsu YC, et al. Frequent epidermal growth factor receptor gene mutations in malignant pleural effusion of lung adenocarcinoma. Eur Respir J. 2008;32:924–30.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by Associazione Italiana per la Ricerca sul Cancro (AIRC) (Grant IG2015 Id.16738 to ML).

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Correspondence to Matteo Landriscina.

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Improta, G., Zupa, A., Natalicchio, M.I. et al. Uncommon frame-shift exon 19 EGFR mutations are sensitive to EGFR tyrosine kinase inhibitors in non-small cell lung carcinoma. Med Oncol 35, 28 (2018). https://doi.org/10.1007/s12032-018-1078-7

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  • DOI: https://doi.org/10.1007/s12032-018-1078-7

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