Combining anti-miR-155 with chemotherapy for the treatment of lung cancers

K. Van Roosbroeck, F. Fanini, T. Setoyama, C. Ivan, C. Rodriguez-Aguayo, E. Fuentes-Mattei, L. Xiao, I. Vannini, R.S. Redis, L. D'Abundo, X. Zhang, M.S. Nicoloso, S. Rossi, V. Gonzalez-Villasana, R. Rupaimoole, M. Ferracin, F. Morabito, A. Neri, P.P. Ruvolo, V.R. RuvoloC.V. Pecot, D. Amadori, L. Abruzzo, S. Calin, X. Wang, M.J. You, A. Ferrajoli, R. Orlowski, W. Plunkett, T.M. Lichtenberg, R.V. Davuluri, I. Berindan-Neagoe, M. Negrini, I.I. Wistuba, H.M. Kantarjian, A.K. Sood, G. Lopez-Berestein, M.J. Keating, M. Fabbri, G.A. Calin

Research output: Contribution to journalArticle

Abstract

Purpose: The oncogenic miR-155 is upregulated in many human cancers, and its expression is increased in more aggressive and therapy-resistant tumors, but the molecular mechanisms underlying miR-155-induced therapy resistance are not fully understood. The main objectives of this study were to determine the role of miR-155 in resistance to chemotherapy and to evaluate anti-miR-155 treatment to chemosensitize tumors. Experimental Design: We performed in vitro studies on cell lines to investigate the role of miR-155 in therapy resistance. To assess the effects of miR-155 inhibition on chemoresistance, we used an in vivo orthotopic lung cancer model of athymic nude mice, which we treated with anti-miR-155 alone or in combination with chemotherapy. To analyze the association of miR-155 expression and the combination of miR-155 and TP53 expression with cancer survival, we studied 956 patients with lung cancer, chronic lymphocytic leukemia, and acute lymphoblastic leukemia. Results: We demonstrate that miR-155 induces resistance to multiple chemotherapeutic agents in vitro, and that downregulation of miR-155 successfully resensitizes tumors to chemotherapy in vivo.Weshow that anti-miR-155-DOPC can be considered nontoxic in vivo. We further demonstrate that miR-155 and TP53 are linked in a negative feedback mechanism and that a combination of high expression of miR-155 and low expression of TP53 is significantly associated with shorter survival in lung cancer. Conclusions: Our findings support the existence of an miR-155/TP53 feedback loop, which is involved in resistance to chemotherapy and which can be specifically targeted to overcome drug resistance, an important cause of cancer-related death. © 2016 American Association for Cancer Research.
Original languageEnglish
Pages (from-to)2891-2904
Number of pages14
JournalClinical Cancer Research
Volume23
Issue number11
DOIs
Publication statusPublished - 2017

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Keywords

  • cisplatin
  • doxorubicin
  • fludarabine
  • microRNA 155
  • animal experiment
  • animal model
  • apoptosis
  • Article
  • binding site
  • cancer combination chemotherapy
  • cancer prognosis
  • cancer resistance
  • cancer survival
  • cell proliferation
  • chemosensitivity
  • down regulation
  • drug efficacy
  • drug response
  • gene expression
  • gene locus
  • gene mutation
  • gene overexpression
  • in vitro study
  • leukemia cell
  • lung cancer
  • male
  • mouse
  • negative feedback
  • nonhuman
  • priority journal

Cite this

Van Roosbroeck, K., Fanini, F., Setoyama, T., Ivan, C., Rodriguez-Aguayo, C., Fuentes-Mattei, E., Xiao, L., Vannini, I., Redis, R. S., D'Abundo, L., Zhang, X., Nicoloso, M. S., Rossi, S., Gonzalez-Villasana, V., Rupaimoole, R., Ferracin, M., Morabito, F., Neri, A., Ruvolo, P. P., ... Calin, G. A. (2017). Combining anti-miR-155 with chemotherapy for the treatment of lung cancers. Clinical Cancer Research, 23(11), 2891-2904. https://doi.org/10.1158/1078-0432.CCR-16-1025