Abstract
Epidermal growth factor receptor (EGFR) mutations are predictive markers for response to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small-cell lung cancer (NSCLC). The most common mutations, exon 19 short deletions and exon 20 point mutation (L858R), activate the tyrosine kinase and confer sensitivity to EGFR-TKIs. However, the function and sensitivity of rare mutations to EGFR-TKIs are unknown. In this study, we found five EGFR mutations out of 16 patients with NSCLC of African-American descent. The frequency of such mutations in this patient population appears to be significantly higher than previously reported. Two of them (N771GY and A767-V769dup) are rare insertion mutations located in exon 20. Using YFP-tagged EGFR mutants, we demonstrated that the mutations confer increased kinase activity, but no sensitivity to erlotinib at clinically available concentrations. In addition, we examined efficacy of PF00299804, an irreversible EGFR-TKI. Although the drug failed to show efficacy to T790M and S768N mutations, the exon 20 insertion mutations were sensitive to PF00299804. These data suggest that rare mutations in exon 20 are resistant to erlotinib but may be sensitive to irreversible inhibitors.
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References
Abramoff MD, Magelhaes PJ, Ram SJ . (2004). Image processing with ImageJ. Biophoton Int 11: 36–42.
Calvo E, Baselga J . (2006). Ethnic differences in response to epidermal growth factor receptor tyrosine kinase inhibitors. J Clin Oncol 24: 2158–2163.
Chen YR, Fu YN, Lin CH, Yang ST, Hu SF, Chen YT et al. (2006). Distinctive activation patterns in constitutively active and gefitinib-sensitive EGFR mutants. Oncogene 25: 1205–1215.
de Gunst MM, Gallegos-Ruiz MI, Giaccone G, Rodriguez JA . (2007). Functional analysis of cancer-associated EGFR mutants using a cellular assay with YFP-tagged EGFR intracellular domain. Mol Cancer 6: 56.
Engelman JA, Zejnullahu K, Gale CM, Lifshits E, Gonzales AJ, Shimamura T et al. (2007). PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res 67: 11924–11932.
Eskens FA, Mom CH, Planting AS, Gietema JA, Amelsberg A, Huisman H et al. (2008). A phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumours. Br J Cancer 98: 80–85.
Han SW, Kim TY, Hwang PG, Jeong S, Kim J, Choi IS et al. (2005). Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol 23: 2493–2501.
Hughes AN, O'Brien ME, Petty WJ, Chick JB, Rankin E, Woll PJ et al. (2009). Overcoming CYP1A1/1A2 mediated induction of metabolism by escalating erlotinib dose in current smokers. J Clin Oncol 27: 1220–1226.
Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, Meyerson M et al. (2005). EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 352: 786–792.
Kosaka T, Yatabe Y, Endoh H, Yoshida K, Hida T, Tsuboi M et al. (2006). Analysis of epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer and acquired resistance to gefitinib. Clin Cancer Res 12: 5764–5769.
Krishnaswamy S, Kanteti R, Duke-Cohan JS, Loganathan S, Liu W, Ma PC et al. (2009). Ethnic differences and functional analysis of MET mutations in lung cancer. Clin Cancer Res 15: 5714–5723.
Leidner RS, Fu P, Clifford B, Hamdan A, Jin C, Eisenberg R et al. (2009). Genetic abnormalities of the EGFR pathway in African American patients with non-small-cell lung cancer. J Clin Oncol 27: 5620–5626.
Mitsudomi T, Kosaka T, Endoh H, Horio Y, Hida T, Mori S et al. (2005). Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence. J Clin Oncol 23: 2513–2520.
Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J et al. (2010). Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 11: 121–128.
Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N et al. (2009). Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361: 947–957.
Niculescu-Duvaz D, Whittaker S, Springer C, Marais R . (2007). The EGF receptor Hokey-Cokey. Cancer Cell 11: 209–211.
Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I et al. (2004). 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 101: 13306–13311.
Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C et al. (2009). Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 361: 958–967.
Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M, Wistuba II et al. (2005). Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 97: 339–346.
Sos ML, Rode HB, Heynck S, Peifer M, Fischer F, Kluter S et al. (2010). Chemogenomic profiling provides insights into the limited activity of irreversible EGFR Inhibitors in tumor cells expressing the T790 M EGFR resistance mutation. Cancer Res 70: 868–874.
Wong KK . (2007). HKI-272 in non small cell lung cancer. Clin Cancer Res 13: s4593–s4596.
Wu JY, Wu SG, Yang CH, Gow CH, Chang YL, Yu CJ et al. (2008). Lung cancer with epidermal growth factor receptor exon 20 mutations is associated with poor gefitinib treatment response. Clin Cancer Res 14: 4877–4882.
Yang SH, Mechanic LE, Yang P, Landi MT, Bowman ED, Wampfler J et al. (2005). Mutations in the tyrosine kinase domain of the epidermal growth factor receptor in non-small cell lung cancer. Clin Cancer Res 11: 2106–2110.
Yun CH, Boggon TJ, Li Y, Woo MS, Greulich H, Meyerson M et al. (2007). Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. Cancer Cell 11: 217–227.
Zhang X, Gureasko J, Shen K, Cole PA, Kuriyan J . (2006). An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell 125: 1137–1149.
Acknowledgements
We thank Dr Xia Di for providing the computer model, and Dr Eva Szabo for patient information.
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Harada, T., Lopez-Chavez, A., Xi, L. et al. Characterization of epidermal growth factor receptor mutations in non-small-cell lung cancer patients of African-American ancestry. Oncogene 30, 1744–1752 (2011). https://doi.org/10.1038/onc.2010.545
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DOI: https://doi.org/10.1038/onc.2010.545
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