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 Aruzzo, Steliana Calin, Xuemei Wang, Mingjian James You, Alessandra Ferrajoli, Robert Z. Orlowski, William Plunkett, Tara M. Lichtenberg, Ramana V. Davuluri, Ioana Berindan-Neagoe, Massimo Negrini, Ignacio I. Wistuba, Kantarjian Hagop, Anil K. Sood, Gabriel Lopez-Berestein, Michael J. Keating, Muller Fabbri, George A. Calin

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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. We show that anti-miR-155-DOPC can be considered non-toxic in vivo. We further demonstrate that miR-155 and TP53 are linked in a negative feedback mechanism, and demonstrate 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 a 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
JournalClinical Cancer Research
DOIs
Publication statusE-pub ahead of print - Nov 30 2016

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  • Journal Article

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    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. (2016). Combining anti-miR-155 with chemotherapy for the treatment of lung cancers. Clinical Cancer Research. https://doi.org/10.1158/1078-0432.CCR-16-1025