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

Katrien Van Roosbroeck, Francesca Fanini, Tetsuro Setoyama, Cristina Ivan, Cristian Rodriguez-Aguayo, Enrique Fuentes-Mattei, Lianchun Xiao, Ivan Vannini, Roxana S. Redis, Lucilla D'Abundo, Xinna Zhang, Milena S. Nicoloso, Simona Rossi, Vianey Gonzalez-Villasana, Rajesha Rupaimoole, Manuela Ferracin, Fortunato Morabito, Antonino Neri, Peter P. Ruvolo, Vivian R. RuvoloChad V. Pecot, Dino Amadori, Lynne Abruzzo, Steliana Calin, Xuemei Wang, M. James You, Alessandra Ferrajoli, Robert Orlowski, William Plunkett, Tara M. Lichtenberg, Ramana V. Davuluri, Ioana Berindan-Neagoe, Massimo Negrini, Ignacio I. Wistuba, Hagop M. Kantarjian, Anil K. Sood, Gabriel Lopez-Berestein, Michael J. Keating, Muller Fabbri, George 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.

Original languageEnglish
Pages (from-to)2891-2904
Number of pages14
JournalClinical Cancer Research
Volume23
Issue number11
DOIs
Publication statusPublished - Jun 1 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • 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