Altered expression of cellular proliferation, apoptosis and the cell cycle-related genes in lung cancer cells with acquired resistance to EGFR tyrosine kinase inhibitors

Lee,Tae‑Gul; Jeong,Eun‑Hui; Min,Il  Jae; Kim,Seo  Yun; Kim,Hye‑Ryoun; Kim,Cheol  Hyeon

doi:10.3892/ol.2017.6428

Altered expression of cellular proliferation, apoptosis and the cell cycle-related genes in lung cancer cells with acquired resistance to EGFR tyrosine kinase inhibitors

Authors:
- Tae‑Gul Lee
- Eun‑Hui Jeong
- Il Jae Min
- Seo Yun Kim
- Hye‑Ryoun Kim
- Cheol Hyeon Kim
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Affiliations: Division of Pulmonology, Department of Internal Medicine, Korea Cancer Center Hospital, Seoul 139‑706, Republic of Korea
Published online on: June 20, 2017 https://doi.org/10.3892/ol.2017.6428
Pages: 2191-2197
Copyright: © Lee et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Non-small cell lung cancers harboring somatic gain-of-function mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain respond well to treatment with EGFR tyrosine kinase inhibitors (TKIs) including gefitinib and erlotinib. However, all patients who experience a marked improvement with these drugs eventually develop disease progression due to the acquisition of drug resistance. Approximately half of the cases with acquired resistance to EGFR TKIs can be accounted for by a second‑site mutation in exon 20 of the EGFR kinase domain (T790M). However, the changes of gene expression involved in EGFR TKI resistance due to the T790M mutation remain poorly defined. The present study established lung cancer cell lines that were resistant to gefitinib or erlotinib, and these cell lines were verified to contain the EGFR T790M mutation. The differential expression of genes associated with acquired resistance was verified in the present study by mRNA microarray analysis. Among the genes whose expression was significantly altered, genes whose expression was altered in gefitinib‑ and erlotinib‑resistant cells were focused on. Notably, a total of 1,617 genes were identified as being differentially expressed in gefitinib‑ and erlotinib‑resistant cells. Indeed, Gene ontology analysis revealed altered expression of genes involved in the regulation of cellular proliferation, apoptosis, and the cell cycle in EGFR TKI‑resistant cells. The present results demonstrate distinctive gene expression patterns of EGFR TKI‑resistant lung cancer cells with the EGFR T790M mutation. The present study can provide key insights into gene expression profiles involved in conferring resistance to EGFR TKI therapy in lung cancer cells.

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1	Hynes NE and Lane HA: ERBB receptors and cancer: The complexity of targeted inhibitors. Nat Rev Cancer. 5:341–344. 2005. View Article : Google Scholar : PubMed/NCBI
2	Pao W and Chmielecki J: Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat Rev Cancer. 10:760–774. 2010. View Article : Google Scholar : PubMed/NCBI
3	Cataldo VD, Gibbons DL, Pérez-Soler R and Quintás-Cardama A: Treatment of non-small-cell lung cancer with erlotinib or gefitinib. N Engl J Med. 364:947–955. 2011. View Article : Google Scholar : PubMed/NCBI
4	Wheeler DL, Dunn EF and Harari PM: Understanding resistance to EGFR inhibitors-impact on future treatment strategies. Nat Rev Clin Oncol. 7:493–507. 2010. View Article : Google Scholar : PubMed/NCBI
5	Kobayashi S, Boggon TJ, Dayaram T, Jänne PA, Kocher O, Meyerson M, Johnson BE, Eck MJ, Tenen DG and Halmos B: EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 352:786–792. 2005. View Article : Google Scholar : PubMed/NCBI
6	Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, Kris MG and Varmus H: Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2:e732005. View Article : Google Scholar : PubMed/NCBI
7	Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong KK, Meyerson M and Eck MJ: The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci USA. 105:pp. 2070–2075. 2008; View Article : Google Scholar : PubMed/NCBI
8	Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, Gale CM, Zhao X, Christensen J, et al: MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 316:1039–1043. 2007. View Article : Google Scholar : PubMed/NCBI
9	Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, Bergethon K, Shaw AT, Gettinger S and Heist RS: Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 3:75ra262011. View Article : Google Scholar : PubMed/NCBI
10	Zakowski MF, Ladanyi M and Kris MG; Memorial Sloan-Kettering Cancer Center Lung Cancer OncoGenome Group, : EGFR mutations in small-cell lung cancers in patients who have never smoked. N Engl J Med. 355:213–215. 2006. View Article : Google Scholar : PubMed/NCBI
11	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
12	Suda K, Tomizawa K, Fujii M, Murakami H, Osada H, Maehara Y, Yatabe Y, Sekido Y and Mitsudomi T: Epithelial to mesenchymal transition in an epidermal growth factor receptor-mutant lung cancer cell line with acquired resistance to erlotinib. J Thorac Oncol. 6:1152–1161. 2011. View Article : Google Scholar : PubMed/NCBI
13	van 't Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, van der Kooy K, Marton MJ, Witteveen AT, et al: Gene expression profiling predicts clinical outcome of breast cancer. Nature. 415:530–536. 2002. View Article : Google Scholar : PubMed/NCBI
14	Ruzzo A, Graziano F, Loupakis F, Rulli E, Canestrari E, Santini D, Catalano V, Ficarelli R, Maltese P and Bisonni R: Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFOX-4 chemotherapy. J Clin Oncol. 25:1247–1254. 2007. View Article : Google Scholar : PubMed/NCBI
15	Ono M, Hirata A, Kometani T, Miyagawa M, Ueda S, Kinoshita H, Fujii T and Kuwano M: Sensitivity to gefitinib (Iressa, ZD1839) in non-small cell lung cancer cell lines correlates with dependence on the epidermal growth factor (EGF) receptor/extracellular signal-regulated kinase 1/2 and EGF receptor/Akt pathway for proliferation. Mol Cancer Ther. 3:465–472. 2004.PubMed/NCBI
16	Rho JK, Choi YJ, Lee JK, Ryoo BY, Na II, Yang SH, Lee SS, Kim CH, Yoo YD and Lee JC: The role of MET activation in determining the sensitivity to epidermal growth factor receptor tyrosine kinase inhibitors. Mol Cancer Res. 7:1736–1743. 2009. View Article : Google Scholar : PubMed/NCBI
17	Lange A, Thon L, Mathieu S and Adam D: The apoptosis inhibitory domain of FE65-like protein 1 regulates both apoptotic and caspase-independent programmed cell death mediated by tumor necrosis factor. Biochem Biophys Res Commun. 335:575–583. 2005. View Article : Google Scholar : PubMed/NCBI
18	Cullis J, Meiri D, Sandi MJ, Radulovich N, Kent OA, Medrano M, Mokady D, Normand J, Larose J, Marcotte R, et al: The RhoGEF GEF-H1 is required for oncogenic RAS signaling via KSR-1. Cancer Cell. 25:181–195. 2014. View Article : Google Scholar : PubMed/NCBI
19	Liao YC, Ruan JW, Lua I, Li MH, Chen WL, Wang JR, Kao RH and Chen JH: Overexpressed hPTTG1 promotes breast cancer cell invasion and metastasis by regulating GEF-H1/RhoA signalling. Oncogene. 31:3086–3097. 2012. View Article : Google Scholar : PubMed/NCBI
20	Engels EA, Wu X, Gu J, Dong Q, Liu J and Spitz MR: Systematic evaluation of genetic variants in the inflammation pathway and risk of lung cancer. Cancer Res. 67:6520–6527. 2007. View Article : Google Scholar : PubMed/NCBI
21	Liu SC, Tsang NM, Chiang WC, Chang KP, Hsueh C, Liang Y, Juang JL, Chow KP and Chang YS: Leukemia inhibitory factor promotes nasopharyngeal carcinoma progression and radioresistance. J Clin Invest. 123:5269–5283. 2013. View Article : Google Scholar : PubMed/NCBI
22	Momand J, Zambetti GP, Olson DC, George D and Levine AJ: The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell. 69:1237–1245. 1992. View Article : Google Scholar : PubMed/NCBI
23	Chew A, Salama P, Robbshaw A, Klopcic B, Zeps N, Platell C and Lawrance IC: SPARC, FOXP3, CD8 and CD45 correlation with disease recurrence and long-term disease-free survival in colorectal cancer. PLoS One. 6:e220472011. View Article : Google Scholar : PubMed/NCBI
24	Li Z, Dong Z, Myer D, Yip-Schneider M, Liu J, Cui P, Schmidt CM and Zhang JT: Role of 14-3-3σ in poor prognosis and in radiation and drug resistance of human pancreatic cancers. BMC Cancer. 10:5982010. View Article : Google Scholar : PubMed/NCBI
25	Shiba-Ishii A and Noguchi M: Aberrant stratifin overexpression is regulated by tumor-associated CpG demethylation in lung adenocarcinoma. Am J Pathol. 180:1653–1662. 2012. View Article : Google Scholar : PubMed/NCBI
26	Carmeliet P: VEGF as a key mediator of angiogenesis in cancer. Oncology. 69 Suppl 3:S4–S10. 2005. View Article : Google Scholar
27	Chen CH, Lai JM, Chou TY, Chen CY, Su LJ, Lee YC, Cheng TS, Hong YR, Chou CK, Whang-Peng J, et al: VEGFA upregulates FLJ10540 and modulates migration and invasion of lung cancer via PI3K/AKT pathway. PLoS One. 4:e50522009. View Article : Google Scholar : PubMed/NCBI
28	Domínguez-Monzón G, Benítez JA, Vergara P, Lorenzana R and Segovia J: Gas1 inhibits cell proliferation and induces apoptosis of human primary gliomas in the absence of Shh. Int J Dev Neurosci. 27:305–313. 2009. View Article : Google Scholar : PubMed/NCBI
29	Zhu J and Chen X: MCG10, a novel p53 target gene that encodes a KH domain RNA-binding protein, is capable of inducing apoptosis and cell cycle arrest in G(2)-M. Mol. Cell Biol. 20:5602–5618. 2000.
30	Carswell EA, Old LJ, Kassel RL, Green S, Fiore N and Williamson B: An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci USA. 72:pp. 3666–3670. 1975; View Article : Google Scholar : PubMed/NCBI
31	Terai H, Soejima K, Yasuda H, Sato T, Naoki K, Ikemura S, Arai D, Ohgino K, Ishioka K, Hamamoto J, et al: Long-term exposure to gefitinib induces acquired resistance through DNA methylation changes in the EGFR-mutant PC9 lung cancer cell line. Int J Oncol. 46:430–436. 2015.PubMed/NCBI