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The role of microRNAs in resistance to targeted treatments of non-small cell lung cancer

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Abstract

Purpose

Non-small cell lung cancer (NSCLC), accounting for the most of lung cancers, is usually diagnosed in advanced stage. Targeted treatments boost advanced NSCLC patients with certain mutations, but early drug resistance blocks the advantages of target medicine. MicroRNAs (miRNAs) are regarded as a cluster of small noncoding and posttranscriptionally negative regulating RNAs. We want to explore the role of miRNAs in resistance to targeted treatments of NSCLC to improve the prognosis.

Methods

We reviewed recent studies about miRNAs and targeted treatment resistance in NSCLC and classified resistance into two types: EGFR-TKIs resistance and ALK-TKIs resistance.

Results and conclusion

Recent studies indicate that miRNAs involve in drug resistance possession in positive and negative manners. Inhibiting expression of certain miRNAs that promote drug resistance and increasing expression of miRNAs that reverse drug resistance may illuminate novel prospect of adjuvant targeted treatments in NSCLC.

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References

  1. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2):281–297

    Article  CAS  PubMed  Google Scholar 

  2. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90

    Article  PubMed  Google Scholar 

  3. García-Campelo R, Bernabé R, Cobo M, Corral J, Coves J, Dómine M, Nadal E, Rodriguez-Abreu D, Viñolas N, Massuti B (2015) SEOM clinical guidelines for the treatment of non-small cell lung cancer (NSCLC) 2015. Clin Transl Oncol 17(12):1020–1029

    Article  PubMed  PubMed Central  Google Scholar 

  4. Bastid J (2012) EMT in carcinoma progression and dissemination: facts, unanswered questions, and clinical considerations. Cancer Metastasis Rev 31(1–2):277–283

    Article  PubMed  Google Scholar 

  5. Scheel C, Weinberg RA (2011) Phenotypic plasticity and epithelial-mesenchymal transitions in cancer and normal stem cells? Int J Cancer 129(10):2310–2314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Xiaofeng Z, Carstens JL, Jiha K, Matthew S, Judith K, Hikaru S, Chia-Chin W, Lebleu VS, Raghu K (2015) Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527(7579):525–530

    Article  Google Scholar 

  7. Fischer KR, Anna D, Sharrell L, Jianting S, Fuhai L, Wong STC, Hyejin C, Tina ER, Seongho R, Juliane T (2015) Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 527(7579):472–476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Jean Paul T, Sleeman JP (2006) Complex networks orchestrate epithelial–mesenchymal transitions. Nat Rev Mol Cell Biol 7(2):131–142

    Article  Google Scholar 

  9. Jiri Z, Böttinger EP (2005) TGF-beta and epithelial-to-mesenchymal transitions. Oncogene 24(37):5764–5774

    Article  Google Scholar 

  10. Kitamura K, Seike M, Okano T, Matsuda K, Miyanaga A, Mizutani H, Noro R, Minegishi Y, Kubota K, Gemma A (2014) MiR-134/487b/655 cluster regulates TGF-β-induced epithelial–mesenchymal transition and drug resistance to gefitinib by targeting MAGI2 in lung adenocarcinoma cells. Mol Cancer Ther 13(2):444–453

    Article  CAS  PubMed  Google Scholar 

  11. Mengru C, Masahiro S, Chie S, Hideaki M, Kazuhiro K, Yuji M, Rintaro N, Akinobu Y, Li C, Akihiko G (2012) MiR-23a regulates TGF-β-induced epithelial–mesenchymal transition by targeting E-cadherin in lung cancer cells. Int J Oncol 41(3):869–875

    Google Scholar 

  12. Engelman JA, Kreshnik Z, Tetsuya M, Youngchul S, Courtney H, Joon OhP, Neal L, Christopher-Michael G, Xiaojun Z, James C (2007) MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316(5827):1039–1043

    Article  CAS  PubMed  Google Scholar 

  13. Garofalo M, Romano G, Leva GD, Nuovo G, Jeon YJ, Ngankeu A, Jin S, Lovat F, Alder H, Condorelli G (2011) EGFR and MET receptor tyrosine kinase-altered microRNA expression induces tumorigenesis and gefitinib resistance in lung cancers. Nat Med 18(1):74–82

    PubMed  PubMed Central  Google Scholar 

  14. Fumarola C, Bonelli MA, Petronini PG, Alfieri RR (2014) Targeting PI3 K/AKT/mTOR pathway in non small cell lung cancer. Biochem Pharmacol 90(3):197–207

    Article  CAS  PubMed  Google Scholar 

  15. Vassiliki P (2012) Development of PI3 K/AKT/mTOR pathway inhibitors and their application in personalized therapy for non-small-cell lung cancer. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer 7(8):1315–1326

    Google Scholar 

  16. Balsara BR, Jianming P, Yasuhiro M, Robert P, Andres KS, Hao W, Michael U, Testa JR (2004) Frequent activation of AKT in non-small cell lung carcinomas and preneoplastic bronchial lesions. Carcinogenesis 25(11):2053–2059

    Article  CAS  PubMed  Google Scholar 

  17. Stefano V, Calin GA, Chang-Gong L, Stefan A, Amelia C, Fabio P, Rosa V, Marilena I, Claudia R, Manuela F (2006) A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA 103(7):2257–2261

    Article  Google Scholar 

  18. Jinsong L, Hongzhang H, Lijuan S, Mei Y, Chaobin P, Weiliang C, Donghui W, Zhaoyu L, Chunxian Z, Yandan Y (2009) MiR-21 indicates poor prognosis in tongue squamous cell carcinomas as an apoptosis inhibitor. Clin Cancer Res Off J Am Assoc Cancer Res 15(12):3998–4008

    Article  Google Scholar 

  19. Hwang JH, Voortman J, Giovannetti E, Steinberg SM, Leon LG, Kim YT, Funel N, Park JK, Kim MA, Kang GH, Kim SW, Del Chiaro M, Peters GJ, Giaccone G (2010) Identification of microRNA-21 as a biomarker for chemoresistance and clinical outcome following adjuvant therapy in resectable pancreatic cancer. PLoS ONE 5(5):65

    Article  Google Scholar 

  20. Zadeh MM, Motamed N, Ranji N, Majidi M, Falahi F (2016) Silibinin-Induced apoptosis and downregulation of MicroRNA-21 and MicroRNA-155 in MCF-7 human breast cancer cells. J Breast Cancer 19(1):45–52

    Article  PubMed  PubMed Central  Google Scholar 

  21. Bing L, Shengxiang R, Xuefei L, Yongsheng W, David G, Songwen Z, Xiaoxia C, Chunxia S, Mo C, Peng K (2013) MiR-21 overexpression is associated with acquired resistance of EGFR-TKI in non-small cell lung cancer. Lung Cancer 83(2):146–153

    Google Scholar 

  22. Matia-Merino L, Singh H (2014) Alteration in Mir-21/PTEN expression modulates gefitinib resistance in non-small cell lung cancer. PLoS ONE 9(7):e103305

    Article  Google Scholar 

  23. Jian-Ya Z, Xi C, Jing Z, Zhang B, Xing C, Pei Z, Zhen-Feng L, Jian-Ying Z (2014) MicroRNA-34a overcomes HGF-mediated gefitinib resistance in EGFR mutant lung cancer cells partly by targeting MET. Cancer Lett 351(2):265–271

    Article  Google Scholar 

  24. Gong LC, Susan MC, Mike G, Cindy T, Yeatman TJ (2014) MicroRNA-147 induces a mesenchymal-to-epithelial transition (MET) and reverses EGFR inhibitor resistance. PLoS ONE 9(1):e84597

    Article  Google Scholar 

  25. Elisa B, Sholl LM, Michael P, John R, Christopher W, Lenora D, Natalie V, Dyane B, Yeap BY, Michelangelo F (2010) Met activation in non-small cell lung cancer is associated with de novo resistance to EGFR inhibitors and the development of brain metastasis. Am J Pathol 177(1):415–423

    Article  Google Scholar 

  26. Agarwal S, Zerillo C, Kolmakova J, Christensen JG, Harris LN, Rimm DL, Digiovanna MP, Stern DF (2009) Association of constitutively activated hepatocyte growth factor receptor (Met) with resistance to a dual EGFR/Her2 inhibitor in non-small-cell lung cancer cells. Br J Cancer 100(6):941–949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhen Q, Liu J, Gao L, Liu J, Wang R, Chu W, Zhang Y, Tan G, Zhao X, Lv B (2015) MicroRNA-200a targets EGFR and c-Met to inhibit migration, invasion, and gefitinib resistance in non-small cell lung cancer. Cytogenet Genome Res 129(10):2310–2314

    Google Scholar 

  28. Ge X, Zheng L, Huang M, Wang Y, Bi F (2014) MicroRNA expression profiles associated with acquired gefitinib-resistance in human lung adenocarcinoma cells. Mol Med Rep 11(1):333–340

    PubMed  Google Scholar 

  29. Gao Y, Fan XW, Li WN, Ping W, Deng Y, Fu XN (2014) miR-138-5p reverses gefitinib resistance in non-small cell lung cancer cells via negatively regulating G protein-coupled receptor 124. Biochem Biophys Res Commun 446(1):179–186

    Article  CAS  PubMed  Google Scholar 

  30. Doebele RC, Pilling AB, Aisner DL, Kutateladze TG, Le AT, Weickhardt AJ, Kondo KL, Linderman DJ, Heasley LE, Franklin WA (2012) Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res 18(5):1472–1482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Shaw AT, Dong-Wan K, Kazuhiko N, Takashi S, Lucio C, Myung-Ju A, Tommaso DP, Benjamin B, Solomon BJ, Fiona B (2013) Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 368(25):2385–2394

    Article  CAS  PubMed  Google Scholar 

  32. Choi YL, Soda M, Yamashita Y et al (2010) EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med 363(18):1734–1739

    Article  CAS  PubMed  Google Scholar 

  33. Doebele RC, Pilling AB, Aisner DL, Kutateladze TG, Le AT, Weickhardt AJ, Kondo KL, Linderman DJ, Heasley LE, Franklin WA, Varella-Garcia M, Camidge DR (2012) Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res Off J Am Assoc Cancer Res 18(5):1472–1482

    Article  CAS  Google Scholar 

  34. Katayama R, Shaw AT, Khan TM, Mino-Kenudson M, Solomon BJ, Halmos B, Jessop NA, Wain JC, Yeo AT, Benes C, Drew L, Saeh JC, Crosby K, Sequist LV, Iafrate AJ, Engelman JA (2012) Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Sci Transl Med 4(120):1409

    Article  Google Scholar 

  35. Dejean E, Renalier MH, Foisseau M, Agirre X, Joseph N, Paiva GR, De Saati T, Soulier J, Desjobert C, Lamant L (2011) Hypoxia-microRNA-16 downregulation induces VEGF expression in anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphomas. Leukemia Off J Leuk Soc Am Leuk Res Fund UK 25(12):1882–1890

    Article  CAS  Google Scholar 

  36. Cécile D, Marie-Hélène R, Julie B, Emilie D, Nicole J, Anna K, Jean S, Estelle E, Fabienne M, Jérome C (2011) MiR-29a down-regulation in ALK-positive anaplastic large cell lymphomas contributes to apoptosis blockade through MCL-1 overexpression. Blood 117(24):6627–6637

    Article  Google Scholar 

  37. Hironori M, Suzuki HI, Hikaru N, Masaaki N, Takashi Y, Norio K, Hiroyuki M, Koichi S, Kohei M (2011) miR-135b mediates NPM-ALK-driven oncogenicity and renders IL-17-producing immunophenotype to anaplastic large cell lymphoma. Blood 118(26):6881–6892

    Article  Google Scholar 

  38. Olaf M, Frank H, Daniela L, Eveline S, Zlatko T, Marcel S, Gerda E, Hassler MR, Christiane T, Ana S (2010) Identification of differential and functionally active miRNAs in both anaplastic lymphoma kinase (ALK)+ and ALK− anaplastic large-cell lymphoma. Proc Natl Acad Sci 107(37):16228–16233

    Article  Google Scholar 

  39. Coralie HA, Thibaud V, Camille D, Cathy Q, Géraldine M, Samuel Q, Jinsong J, Salvatore S, Pierre F, Monica C (2015) Reversal of microRNA-150 silencing disadvantages crizotinib-resistant NPM-ALK(+) cell growth. J Clin Investig 125(9):3505–3518

    Article  Google Scholar 

  40. Inamura K, Ishikawa Y (2016) MicroRNA in lung cancer: novel biomarkers and potential tools for treatment. J Clin Med. doi:10.3390/jcm5030036

    PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by the National Natural Science Foundations of China (Nos: 81272566; 81472773).

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Authors and Affiliations

  1. Department of Pathology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China

    Hongjing Zang, Weiyuan Wang & Songqing Fan

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  1. Hongjing Zang
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Correspondence to Songqing Fan.

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Zang, H., Wang, W. & Fan, S. The role of microRNAs in resistance to targeted treatments of non-small cell lung cancer. Cancer Chemother Pharmacol 79, 227–231 (2017). https://doi.org/10.1007/s00280-016-3130-7

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  • DOI: https://doi.org/10.1007/s00280-016-3130-7

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