Resistance to epithelial growth factor receptor tyrosine kinase inhibitors in a patient with transformation from lung adenocarcinoma to small cell lung cancer: A case report

Fang,Liying; He,Jian; Xia,Jingwen; Dong,Liang; Zhang,Xiujuan; Chai,Yaqin; Li,Ying; Niu,Mengjie; Hang,Tianxing; Li,Shengqing

doi:10.3892/ol.2017.6229

Resistance to epithelial growth factor receptor tyrosine kinase inhibitors in a patient with transformation from lung adenocarcinoma to small cell lung cancer: A case report

Authors:
- Liying Fang
- Jian He
- Jingwen Xia
- Liang Dong
- Xiujuan Zhang
- Yaqin Chai
- Ying Li
- Mengjie Niu
- Tianxing Hang
- Shengqing Li
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Affiliations: Department of Respiratory Medicine, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
Published online on: May 23, 2017 https://doi.org/10.3892/ol.2017.6229
Pages: 593-598
Copyright: © Fang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

First-generation epithelial growth factor receptor tyrosine kinase inhibitors (EGFR‑TKIs) have markedly improved the treatment of non-small cell lung cancer (non‑SCLC) with EGFR‑sensitive mutations. However, acquired resistance to these drugs was inevitable. The transformation of lung adenocarcinoma to SCLC following treatment with EGFR‑TKIs is a rare phenomenon that contributes to resistance to EGFR‑TKIs. The present case concerns a 74‑year‑old man previously diagnosed with and treated for pneumonia; however, this was later pathologically confirmed as lung adenocarcinoma by transbronchial lung biopsy. Deletion of exon 19 of EGFR was identified by next‑generation sequencing technology. The patient improved markedly when treated with gefitinib, but relapsed after 1 year, with markedly increased serum levels of neuron-specific enolase (NSE). Transformation to SCLC was detected by endobronchial ultrasound transbronchial needle aspiration (EBUS‑TBNA) re‑biopsy, which was negative for the deletion of exon 19 of EGFR. The patient was positive for vimentin expression and refractory to etoposide and cisplatin chemotherapy, and succumbed to the disease 18 months after diagnosis. Transformation of the disease from adenocarcinoma to SCLC may have been due to cancer heterogeneity. Re‑biopsy is therefore important in EGFR‑TKI‑resistant patients for genetic and histological re‑evaluation. NSE serum levels may also be useful for detecting early SCLC transformation.

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1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2015. CA Cancer J Clin. 65:5–29. 2015. View Article : Google Scholar : PubMed/NCBI
2	Wakelee H and Belani CP: Optimizing first-line treatment options for patients with advanced NSCLC. Oncologist. 10 Suppl 3:S1–S10. 2005. View Article : Google Scholar
3	Wu JY, Wu SG, Yang CH, Chang YL, Chang YC, Hsu YC, Shih JY and Yang PC: Comparison of gefitinib and erlotinib in advanced NSCLC and the effect of EGFR mutations. Lung Cancer. 72:205–212. 2011. View Article : Google Scholar : PubMed/NCBI
4	Xu M, Xie Y, Ni S and Liu H: The latest therapeutic strategies after resistance to first generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in patients with non-small cell lung cancer (NSCLC). Ann Transl Med. 3:962015.PubMed/NCBI
5	Camidge DR, Pao W and Sequist LV: Acquired resistance to TKIs in solid tumours: Learning from lung cancer. Nat Rev Clin Oncol. 11:473–481. 2014. View Article : Google Scholar : PubMed/NCBI
6	Li W, Ren S, Li J, Li A, Fan L, Li X, Zhao C, He Y, Gao G, Chen X, et al: T790M mutation is associated with better efficacy of treatment beyond progression with EGFR-TKI in advanced NSCLC patients. Lung Cancer. 84:295–300. 2014. View Article : Google Scholar : PubMed/NCBI
7	Brugger W and Thomas M: EGFR-TKI resistant non-small cell lung cancer (NSCLC): New developments and implications for future treatment. Lung Cancer. 77:2–8. 2012. View Article : Google Scholar : PubMed/NCBI
8	Cretella D, Saccani F, Quaini F, Frati C, Lagrasta C, Bonelli M, Caffarra C, Cavazzoni A, Fumarola C, Galetti M, et al: Trastuzumab emtansine is active on HER-2 overexpressing NSCLC cell lines and overcomes gefitinib resistance. Mol Cancer. 13:1432014. View Article : Google Scholar : PubMed/NCBI
9	Lin Y, Wang X and Jin H: EGFR-TKI resistance in NSCLC patients: Mechanisms and strategies. Am J Cancer Res. 4:411–435. 2014.PubMed/NCBI
10	Li Y, Yang Z, Li W, Xu S, Wang T, Wang T, Niu M, Zhang S, Jia L and Li S: TOPK promotes lung cancer resistance to EGFR tyrosine kinase inhibitors by phosphorylating and activating c-Jun. Oncotarget. 7:6748–6764. 2016.PubMed/NCBI
11	Rudisch A, Dewhurst MR, Horga LG, Kramer N, Harrer N, Dong M, van der Kuip H, Wernitznig A, Bernthaler A, Dolznig H and Sommergruber W: High EMT signature score of invasive non-small cell lung cancer (NSCLC) cells correlates with NFκB driven colony-stimulating factor 2 (CSF2/GM-CSF) secretion by neighboring stromal fibroblasts. PLoS One. 10:e01242832015. View Article : Google Scholar : PubMed/NCBI
12	Jiang SY, Zhao J, Wang MZ, Huo Z, Zhang J, Zhong W and Xu Y: Small-cell lung cancer transformation in patients with pulmonary adenocarcinoma: A case report and review of literature. Medicine (Baltimore). 95:e27522016. View Article : Google Scholar : PubMed/NCBI
13	Watanabe S, Sone T, Matsui T, Yamamura K, Tani M, Okazaki A, Kurokawa K, Tambo Y, Takato H, Ohkura N, et al: Transformation to small-cell lung cancer following treatment with EGFR tyrosine kinase inhibitors in a patient with lung adenocarcinoma. Lung Cancer. 82:370–372. 2013. View Article : Google Scholar : PubMed/NCBI
14	Oser MG, Niederst MJ, Sequist LV and Engelman JA: Transformation from non-small-cell lung cancer to small-cell lung cancer: Molecular drivers and cells of origin. Lancet Oncol. 16:e165–e172. 2015. View Article : Google Scholar : PubMed/NCBI
15	Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, Kris MG, Miller VA, Ladanyi M and Riely GJ: 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. 19:2240–2247. 2013. View Article : Google Scholar : PubMed/NCBI
16	Wu SG, Liu YN, Tsai MF, Chang YL, Yu CJ, Yang PC, Yang JC, Wen YF and Shih JY: The mechanism of acquired resistance to irreversible EGFR tyrosine kinase inhibitor-afatinib in lung adenocarcinoma patients. Oncotarget. 7:12404–12413. 2016.PubMed/NCBI
17	de Bruin EC, McGranahan N, Mitter R, Salm M, Wedge DC, Yates L, Jamal-Hanjani M, Shafi S, Murugaesu N, Rowan AJ, et al: Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science. 346:251–256. 2014. View Article : Google Scholar : PubMed/NCBI
18	McGranahan N, Favero F, De Bruin EC, Birkbak NJ, Szallasi Z and Swanton C: Clonal status of actionable driver events and the timing of mutational processes in cancer evolution. Sci Transl Med. 7:283ra542015. View Article : Google Scholar : PubMed/NCBI
19	Zhang J, Fujimoto J, Zhang J, Wedge DC, Song X, Zhang J, Seth S, Chow CW, Cao Y, Gumbs C, et al: Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing. Science. 346:256–259. 2014. View Article : Google Scholar : PubMed/NCBI
20	Uramoto H, Yamada S and Hanagiri T: Clinicopathological characteristics of resected adenosquamous cell carcinoma of the lung: Risk of coexistent double cancer. J Cardiothorac Surg. 5:922010. View Article : Google Scholar : PubMed/NCBI
21	Adelstein DJ, Tomashefski JF Jr, Snow NJ, Horrigan TP and Hines JD: Mixed small cell and non-small cell lung cancer. Chest. 89:699–704. 1986. View Article : Google Scholar : PubMed/NCBI
22	Mangum MD, Greco FA, Hainsworth JD, Hande KR and Johnson DH: Combined small-cell and non-small-cell lung cancer. J Clin Oncol. 7:607–612. 1989. View Article : Google Scholar : PubMed/NCBI
23	Kim WJ, Kim S, Choi H, Chang J, Shin HJ, Park CK, Oh IJ, Kim KS, Kim YC and Choi YD: Histological transformation from non-small cell to small cell lung carcinoma after treatment with epidermal growth factor receptor-tyrosine kinase inhibitor. Thorac Cancer. 6:800–804. 2015. View Article : Google Scholar : PubMed/NCBI
24	Niederst MJ, Sequist LV, Poirier JT, Mermel CH, Lockerman EL, Garcia AR, Katayama R, Costa C, Ross KN, Moran T, et al: RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer. Nat Commun. 6:63772015. View Article : Google Scholar : PubMed/NCBI
25	Chang Y, Kim SY, Choi YJ, So KS, Rho JK, Kim WS, Lee JC, Chung JH and Choi CM: Neuroendocrine differentiation in acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor. Tuberc Respir Dis (Seoul). 75:95–103. 2013. View Article : Google Scholar : PubMed/NCBI
26	Zhang Y, Li XY, Tang Y, Xu Y, Guo WH, Li YC, Liu XK, Huang CY, Wang YS and Wei YQ: Rapid increase of serum neuron specific enolase level and tachyphylaxis of EGFR-tyrosine kinase inhibitor indicate small cell lung cancer transformation from EGFR positive lung adenocarcinoma? Lung Cancer. 81:302–305. 2013. View Article : Google Scholar : PubMed/NCBI
27	Hwang KE, Jung JW, Oh SJ, Park MJ, Shon YJ, Choi KH, Jeong ET and Kim HR: Transformation to small cell lung cancer as an acquired resistance mechanism in EGFR-mutant lung adenocarcinoma: A case report of complete response to etoposide and cisplatin. Tumori. 101:e96–e98. 2015.PubMed/NCBI
28	Molenaar WM, Oosterhuis JW, Oosterhuis AM and Ramaekers FC: Mesenchymal and muscle-specific intermediate filaments (vimentin and desmin) in relation to differentiation in childhood rhabdomyosarcomas. Hum Pathol. 16:838–843. 1985. View Article : Google Scholar : PubMed/NCBI
29	Kidd ME, Shumaker DK and Ridge KM: The role of vimentin intermediate filaments in the progression of lung cancer. Am J Respir Cell Mol Biol. 50:1–6. 2014.PubMed/NCBI
30	Al-Saad S, Al-Shibli K, Donnem T, Persson M, Bremnes RM and Busund LT: The prognostic impact of NF-kappaB p105, vimentin, E-cadherin and Par6 expression in epithelial and stromal compartment in non-small-cell lung cancer. Br J Cancer. 99:1476–1483. 2008. View Article : Google Scholar : PubMed/NCBI
31	Tadokoro A, Kanaji N, Liu D, Yokomise H, Haba R, Ishii T, Takagi T, Watanabe N, Kita N, Kadowaki N and Bandoh S: Vimentin regulates invasiveness and is a poor prognostic marker in non-small cell lung cancer. Anticancer Res. 36:1545–1551. 2016.PubMed/NCBI
32	Liu CY, Lin HH, Tang MJ and Wang YK: Vimentin contributes to epithelial-mesenchymal transition cancer cell mechanics by mediating cytoskeletal organization and focal adhesion maturation. Oncotarget. 6:15966–15983. 2015. View Article : Google Scholar : PubMed/NCBI
33	Pan Y and Li X, Duan J, Yuan L, Fan S, Fan J, Xiaokaiti Y, Yang H, Wang Y and Li X: Enoxaparin sensitizes human non-small-cell lung carcinomas to gefitinib by inhibiting DOCK1 expression, vimentin phosphorylation and Akt activation. Mol Pharmacol. 87:378–390. 2015. View Article : Google Scholar : PubMed/NCBI
34	Satelli A and Li S: Vimentin in cancer and its potential as a molecular target for cancer therapy. Cell Mol Life Sci. 68:3033–3046. 2011. View Article : Google Scholar : PubMed/NCBI
35	Lahat G, Zhu QS, Huang KL, Wang S, Bolshakov S, Liu J, Torres K, Langley RR, Lazar AJ, Hung MC and Lev D: Vimentin is a novel anti-cancer therapeutic target; insights from in vitro and in vivo mice xenograft studies. PLoS One. 5:e101052010. View Article : Google Scholar : PubMed/NCBI
36	Richardson F, Young GD, Sennello R, Wolf J, Argast GM, Mercado P, Davies A, Epstein DM and Wacker B: The evaluation of E-Cadherin and vimentin as biomarkers of clinical outcomes among patients with non-small cell lung cancer treated with erlotinib as second- or third-line therapy. Anticancer Res. 32:537–552. 2012.PubMed/NCBI