Combining Anti-Mir-155 with Chemotherapy for the Treatment of Lung Cancers

Van Roosbroeck, Katrien y Fanini, Francesca y Setoyama, Tetsuro y Ivan, Cristina y Rodríguez Aguayo, Cristian y Fuentes Mattei, Enrique y Xiao, Lianchun y Vannini, Ivan y Redis, Roxana S. y D'Abundo, Lucilla y Zhang, Xinna y Nicoloso, Milena S. y Rossi, Simona y González Villasana, Vianey y Rupaimoole, Rajesha y Ferracin, Manuela y Morabito, Fortunato y Neri, Antonino y Ruvolo, Peter P. y Ruvolo, Vivian R. y Pecot, Chad V. y Amadori, Dino y Abruzzo, Lynne V. y Calin, Steliana y Wang, Xuemei y You, M. James y Ferrajoli, Alessandra y Orlowski, Robert y Plunkett, William y Lichtenberg, Tara M. y Davuluri, Ramana V. y Berindan Neagoe, Ioana y Negrini, Massimo y Wistuba, Ignacio I. y Kantarjian, Hagop M. y Sood, Anil K. y Lopez Berestein, Gabriel y Keating, Michael J. y Fabbri, L. Muller y Calin, George A. (2016) Combining Anti-Mir-155 with Chemotherapy for the Treatment of Lung Cancers. Clinical Cancer Research, 23 (11). pp. 2891-2904. ISSN 1078-0432

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Abstract Purpose: The oncogenic miR-155 is upregulated in many humancancers,anditsexpressionisincreasedinmoreaggressive 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 theroleofmiR-155inresistancetochemotherapyandtoevaluate 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 expressionandthecombinationofmiR-155andTP53expression 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 downregulationofmiR-155successfullyresensitizestumorstochemotherapy invivo.Weshowthatanti-miR-155-DOPCcanbeconsiderednontoxic in vivo. We further demonstrate that miR-155 and TP53 are linkedinanegativefeedbackmechanismandthatacombination 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 miR155/TP53 feedback loop, which is involved in resistance to chemotherapy and which can be specifically targeted to overcomedrugresistance,animportantcauseofcancer-relateddeath. Clin Cancer Res; 23(11); 2891–904. �2016 AACR.

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