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Article

Sensitivity to chemotherapeutics of NSCLC cells with acquired resistance to EGFR-TKIs is mediated by T790M mutation or epithelial-mesenchymal transition

  • Authors:
    • Juan Zhou
    • Qiaoting Hu
    • Xi Zhang
    • Jihua Zheng
    • Bo Xie
    • Zhiyong Xu
    • Weimin Zhang
  • View Affiliations / Copyright

    Affiliations: Department of Oncology, The General Hospital of Guangzhou Military Command of The People's Liberation Army (PLA), Guangzhou, Guangdong 510010, P.R. China
  • Pages: 1783-1792
    |
    Published online on: February 1, 2018
       https://doi.org/10.3892/or.2018.6242
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Abstract

Chemotherapy is one of the methods to treat patients with non-small cell lung cancer (NSCLC) developing resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib. Previous studies revealed that the sensitivity to chemotherapy may depend on different cellular mechanisms of acquired EGFR-TKIs resistance. Thus, the present study aimed to investigate the sensitivity of distinct gefitinib-resistant NSCLC cell lines to chemotherapy in order to help select effective treatment regimens for patients with EGFR-TKI resistance. In the present study, we established two gefitinib-resistant cell lines (PC-9/ZD and PC-9/GR) with the human lung adenocarcinoma cell line PC-9 (carrying the delE746-A750 mutation in the EGFR gene). PC-9/ZD cell line expressed the T790M mutation, while PC-9/GR presented the phenotypes of epithelial to mesenchymal transition (EMT). PC-9/ZD cells were more sensitive to paclitaxel and docetaxel than PC-9 cells and knockdown of T790M decreased this sensitivity. In addition, PC-9/GR cells were less sensitive to chemotherapeutic drugs tested, including cisplatin, gemcitabine, pemetrexed, paclitaxel and docetaxel, compared to PC-9 and PC-9/ZD cells. CDH1 transfection reversed the EMT and restored the sensitivity to chemotherapy in PC-9/GR cells. Furthermore, PC-9 cells became resistant to chemotherapy after TGF-β1-induced EMT. The EMT in NSCLC cells significantly increased cancer stem cell (CSC) properties and tumorgenicity. Collectively, the present study revealed that gefitinib-resistant NSCLC cells carrying the T790M mutation were sensitive to taxane chemotherapy, indicating that T790M is a useful biomarker for the selection of chemotherapy. EMT in NSCLC cells confers resistance to chemotherapy, which may be associated with enhanced CSC properties.
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1 

Stewart EL, Tan SZ, Liu G and Tsao MS: Known and putative mechanisms of resistance to EGFR targeted therapies in NSCLC patients with EGFR mutations - a review. Transl Lung Cancer Res. 4:67–81. 2015.PubMed/NCBI

2 

Jakobsen KR, Demuth C, Sorensen BS and Nielsen AL: The role of epithelial to mesenchymal transition in resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Transl Lung Cancer Res. 5:172–182. 2016. View Article : Google Scholar : PubMed/NCBI

3 

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

4 

Kuo CH, Lin SM, Lee KY, Chung FT, Hsieh MH, Fang YF, Yu CT and Kuo HP: Subsequent chemotherapy improves survival outcome in advanced non-small-cell lung cancer with acquired tyrosine kinase inhibitor resistance. Clin Lung Cancer. 11:51–56. 2010. View Article : Google Scholar : PubMed/NCBI

5 

Rosell R, Molina-Vila MA, Taron M, Bertran-Alamillo J, Mayo C, Vergnenegre A, De Marinis F, Massuti B, De Castro J, Gervais R, et al: EGFR compound mutants and survival on erlotinib in non-small cell lung cancer (NSCLC) patients (p) in the EURTAC study. J Clin Oncol. 30 15 Suppl:S75222012.

6 

Shintani Y, Okimura A, Sato K, Nakagiri T, Kadota Y, Inoue M, Sawabata N, Minami M, Ikeda N, Kawahara K, et al: Epithelial to mesenchymal transition is a determinant of sensitivity to chemoradiotherapy in non-small cell lung cancer. Ann Thorac Surg. 92:1794–1804. 2011. View Article : Google Scholar : PubMed/NCBI

7 

Zhou J, Wang J, Zeng Y, Zhang X, Hu Q, Zheng J, Chen B, Xie B and Zhang WM: Implication of epithelial-mesenchymal transition in IGF1R-induced resistance to EGFR-TKIs in advanced non-small cell lung cancer. Oncotarget. 6:44332–44345. 2015. View Article : Google Scholar : PubMed/NCBI

8 

Chen G, Kronenberger P, Teugels E, Umelo IA and De Grève J: Effect of siRNAs targeting the EGFR T790M mutation in a non-small cell lung cancer cell line resistant to EGFR tyrosine kinase inhibitors and combination with various agents. Biochem Biophys Res Commun. 431:623–629. 2013. View Article : Google Scholar : PubMed/NCBI

9 

Chen G, Kronenberger P, Teugels E, Umelo IA and De Grève J: Targeting the epidermal growth factor receptor in non-small cell lung cancer cells: The effect of combining RNA interference with tyrosine kinase inhibitors or cetuximab. BMC Med. 10:282012. View Article : Google Scholar : PubMed/NCBI

10 

Chen G, Kronenberger P, Umelo IA, Teugels E and De Grève J: Quantification of epidermal growth factor receptor T790M mutant transcripts in lung cancer cells by real-time reverse transcriptase-quantitative polymerase chain reaction. Anal Biochem. 398:266–268. 2010. View Article : Google Scholar : PubMed/NCBI

11 

Ogino A, Kitao H, Hirano S, Uchida A, Ishiai M, Kozuki T, Takigawa N, Takata M, Kiura K and Tanimoto M: Emergence of epidermal growth factor receptor T790M mutation during chronic exposure to gefitinib in a non small cell lung cancer cell line. Cancer Res. 67:7807–7814. 2007. View Article : Google Scholar : PubMed/NCBI

12 

Cheng H, An SJ, Dong S, Zhang YF, Zhang XC, Chen ZH, Jian Su and Wu YL: Molecular mechanism of the schedule-dependent synergistic interaction in EGFR-mutant non-small cell lung cancer cell lines treated with paclitaxel and gefitinib. J Hematol Oncol. 4:52011. View Article : Google Scholar : PubMed/NCBI

13 

Rho JK, Choi YJ, Lee JK, Ryoo BY, Na II, Yang SH, Kim CH and Lee JC: Epithelial to mesenchymal transition derived from repeated exposure to gefitinib determines the sensitivity to EGFR inhibitors in A549, a non-small cell lung cancer cell line. Lung Cancer. 63:219–226. 2009. View Article : Google Scholar : PubMed/NCBI

14 

Mittal V: Epithelial mesenchymal transition in aggressive lung cancers. Adv Exp Med Biol. 890:37–56. 2016. View Article : Google Scholar : PubMed/NCBI

15 

Yin H, Wang Y, Chen W, Zhong S, Liu Z and Zhao J: Drug-resistant CXCR4-positive cells have the molecular characteristics of EMT in NSCLC. Gene. 594:23–29. 2016. View Article : Google Scholar : PubMed/NCBI

16 

Rastogi I, Rajanna S, Webb A, Chhabra G, Foster B, Webb B and Puri N: Mechanism of c-Met and EGFR tyrosine kinase inhibitor resistance through epithelial mesenchymal transition in non-small cell lung cancer. Biochem Biophys Res Commun. 477:937–944. 2016. View Article : Google Scholar : PubMed/NCBI

17 

Wang Z, Li Y, Kong D, Banerjee S, Ahmad A, Azmi AS, Ali S, Abbruzzese JL, Gallick GE and Sarkar FH: Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway. Cancer Res. 69:2400–2407. 2009. View Article : Google Scholar : PubMed/NCBI

18 

Yang AD, Fan F, Camp ER, van Buren G, Liu W, Somcio R, Gray MJ, Cheng H, Hoff PM and Ellis LM: Chronic oxaliplatin resistance induces epithelial-to-mesenchymal transition in colorectal cancer cell lines. Clin Cancer Res. 12:4147–4153. 2006. View Article : Google Scholar : PubMed/NCBI

19 

Kajiyama H, Shibata K, Terauchi M, Yamashita M, Ino K, Nawa A and Kikkawa F: Chemoresistance to paclitaxel induces epithelial-mesenchymal transition and enhances metastatic potential for epithelial ovarian carcinoma cells. Int J Oncol. 31:277–283. 2007.PubMed/NCBI

20 

Shien K, Toyooka S, Yamamoto H, Soh J, Jida M, Thu KL, Hashida S, Maki Y, Ichihara E, Asano H, et al: Acquired resistance to EGFR inhibitors is associated with a manifestation of stem cell-like properties in cancer cells. Cancer Res. 73:3051–3061. 2013. View Article : Google Scholar : PubMed/NCBI

21 

Polyak K and Weinberg RA: Transitions between epithelial and mesenchymal states: Acquisition of malignant and stem cell traits. Nat Rev Cancer. 9:265–273. 2009. View Article : Google Scholar : PubMed/NCBI

22 

Floor S, van Staveren WC, Larsimont D, Dumont JE and Maenhaut C: Cancer cells in epithelial-to-mesenchymal transition and tumor-propagating-cancer stem cells: Distinct, overlapping or same populations. Oncogene. 30:4609–4621. 2011. View Article : Google Scholar : PubMed/NCBI

23 

Chiou SH, Wang ML, Chou YT, Chen CJ, Hong CF, Hsieh WJ, Chang HT, Chen YS, Lin TW, Hsu HS and Wu CW: Coexpression of Oct4 and Nanog enhances malignancy in lung adenocarcinoma by inducing cancer stem cell-like properties and epithelial-mesenchymal transdifferentiation. Cancer Res. 70:10433–10444. 2010. View Article : Google Scholar : PubMed/NCBI

24 

Pirozzi G, Tirino V, Camerlingo R, Franco R, La Rocca A, Liguori E, Martucci N, Paino F, Normanno N and Rocco G: Epithelial to mesenchymal transition by TGFβ-1 induction increases stemness characteristics in primary non small cell lung cancer cell line. PLoS One. 6:e215482011. View Article : Google Scholar : PubMed/NCBI

25 

Hu J, Qiu M, Jiang F, Zhang S, Yang X, Wang J, Xu L and Yin R: MiR-145 regulates cancer stem-like properties and epithelial-to-mesenchymal transition in lung adenocarcinoma-initiating cells. Tumour Biol. 35:8953–8961. 2014. View Article : Google Scholar : PubMed/NCBI

26 

Kuwano M, Sonoda K, Murakami Y, Watari K and Ono M: Overcoming drug resistance to receptor tyrosine kinase inhibitors: Learning from lung cancer. Pharmacol Ther. 161:97–110. 2016. View Article : Google Scholar : PubMed/NCBI

27 

Pirazzoli V, Ayeni D, Meador CB, Sanganahalli BG, Hyder F, de Stanchina E, Goldberg SB, Pao W and Politi K: Afatinib plus cetuximab delays resistance compared to single-agent erlotinib or afatinib in mouse models of TKI-Naïve EGFR L858R-induced lung adenocarcinoma. Clin Cancer Res. 22:426–435. 2016. View Article : Google Scholar : PubMed/NCBI

28 

Wang Y, Singh R, Wang L, Nilsson M, Goonatilake R, Tong P, Li L, Giri U, Villalobos P, Mino B, et al: Polo-like kinase 1 inhibition diminishes acquired resistance to epidermal growth factor receptor inhibition in non-small cell lung cancer with T790M mutations. Oncotarget. 7:47998–48010. 2016.PubMed/NCBI

29 

Leung EL, Fan XX, Wong MP, Jiang ZH, Liu ZQ, Yao XJ, Lu LL, Zhou YL, Yau LF, Tin VP and Liu L: Targeting tyrosine kinase inhibitor-resistant Non-small cell lung cancer by inducing epidermal growth factor receptor degradation via methionine 790 oxidation. Antioxid Redox Signal. 24:263–279. 2016. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Zhou J, Hu Q, Zhang X, Zheng J, Xie B, Xu Z and Zhang W: Sensitivity to chemotherapeutics of NSCLC cells with acquired resistance to EGFR-TKIs is mediated by T790M mutation or epithelial-mesenchymal transition. Oncol Rep 39: 1783-1792, 2018.
APA
Zhou, J., Hu, Q., Zhang, X., Zheng, J., Xie, B., Xu, Z., & Zhang, W. (2018). Sensitivity to chemotherapeutics of NSCLC cells with acquired resistance to EGFR-TKIs is mediated by T790M mutation or epithelial-mesenchymal transition. Oncology Reports, 39, 1783-1792. https://doi.org/10.3892/or.2018.6242
MLA
Zhou, J., Hu, Q., Zhang, X., Zheng, J., Xie, B., Xu, Z., Zhang, W."Sensitivity to chemotherapeutics of NSCLC cells with acquired resistance to EGFR-TKIs is mediated by T790M mutation or epithelial-mesenchymal transition". Oncology Reports 39.4 (2018): 1783-1792.
Chicago
Zhou, J., Hu, Q., Zhang, X., Zheng, J., Xie, B., Xu, Z., Zhang, W."Sensitivity to chemotherapeutics of NSCLC cells with acquired resistance to EGFR-TKIs is mediated by T790M mutation or epithelial-mesenchymal transition". Oncology Reports 39, no. 4 (2018): 1783-1792. https://doi.org/10.3892/or.2018.6242
Copy and paste a formatted citation
x
Spandidos Publications style
Zhou J, Hu Q, Zhang X, Zheng J, Xie B, Xu Z and Zhang W: Sensitivity to chemotherapeutics of NSCLC cells with acquired resistance to EGFR-TKIs is mediated by T790M mutation or epithelial-mesenchymal transition. Oncol Rep 39: 1783-1792, 2018.
APA
Zhou, J., Hu, Q., Zhang, X., Zheng, J., Xie, B., Xu, Z., & Zhang, W. (2018). Sensitivity to chemotherapeutics of NSCLC cells with acquired resistance to EGFR-TKIs is mediated by T790M mutation or epithelial-mesenchymal transition. Oncology Reports, 39, 1783-1792. https://doi.org/10.3892/or.2018.6242
MLA
Zhou, J., Hu, Q., Zhang, X., Zheng, J., Xie, B., Xu, Z., Zhang, W."Sensitivity to chemotherapeutics of NSCLC cells with acquired resistance to EGFR-TKIs is mediated by T790M mutation or epithelial-mesenchymal transition". Oncology Reports 39.4 (2018): 1783-1792.
Chicago
Zhou, J., Hu, Q., Zhang, X., Zheng, J., Xie, B., Xu, Z., Zhang, W."Sensitivity to chemotherapeutics of NSCLC cells with acquired resistance to EGFR-TKIs is mediated by T790M mutation or epithelial-mesenchymal transition". Oncology Reports 39, no. 4 (2018): 1783-1792. https://doi.org/10.3892/or.2018.6242
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