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

Abstract

<b>Purpose:</b> 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.<b>Experimental Design:</b> We performed <i>in vitro</i> 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 <i>in vivo</i> 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 <i>TP53</i> expression with cancer survival, we studied 956 patients with lung cancer, chronic lymphocytic leukemia, and acute lymphoblastic leukemia.<b>Results:</b> We demonstrate that miR-155 induces resistance to multiple chemotherapeutic agents <i>in vitro</i>, and that downregulation of miR-155 successfully resensitizes tumors to chemotherapy <i>in vivo</i> We show that anti-miR-155-DOPC can be considered non-toxic <i>in vivo</i> We further demonstrate that miR-155 and <i>TP53</i> are linked in a negative feedback mechanism and that a combination of high expression of miR-155 and low expression of <i>TP53</i> is significantly associated with shorter survival in lung cancer.<b>Conclusions:</b> 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. <i>Clin Cancer Res; 23(11); 2891-904. ©2016 AACR</i>.