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

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. 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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Lung Neoplasms
Drug Therapy
Neoplasms
Nude Mice
Therapeutics
Survival
B-Cell Chronic Lymphocytic Leukemia
Combination Drug Therapy
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Drug Resistance
Research Design
Down-Regulation
Cell Line
In Vitro Techniques

Keywords

  • Journal Article

Cite this

Van Roosbroeck, K., Fanini, F., Setoyama, T., Ivan, C., Rodriguez-Aguayo, C., Fuentes-Mattei, E., ... 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

Combining anti-miR-155 with chemotherapy for the treatment of lung cancers. / Van Roosbroeck, Katrien; Fanini, Francesca; Setoyama, Tetsuro; Ivan, Cristina; Rodriguez-Aguayo, Cristian; Fuentes-Mattei, Enrique; Xiao, Lianchun; Vannini, Ivan; Redis, Roxana S.; D'Abundo, Lucilla; Zhang, Xinna; Nicoloso, Milena S; Rossi, Simona; Gonzalez-Villasana, Vianey; Rupaimoole, Rajesha; Ferracin, Manuela; Morabito, Fortunato; Neri, Antonino; Ruvolo, Peter P.; Ruvolo, Vivian R; Pecot, Chad V.; Amadori, Dino; Aruzzo, Lynne; Calin, Steliana; Wang, Xuemei; You, Mingjian James; Ferrajoli, Alessandra; Orlowski, Robert Z.; Plunkett, William; Lichtenberg, Tara M.; Davuluri, Ramana V.; Berindan-Neagoe, Ioana; Negrini, Massimo; Wistuba, Ignacio I.; Hagop, Kantarjian; Sood, Anil K.; Lopez-Berestein, Gabriel; Keating, Michael J.; Fabbri, Muller; Calin, George A.

In: Clinical Cancer Research, 30.11.2016.

Research output: Contribution to journalArticle

Van Roosbroeck, K, Fanini, F, Setoyama, T, Ivan, C, Rodriguez-Aguayo, C, Fuentes-Mattei, E, Xiao, L, Vannini, I, Redis, RS, D'Abundo, L, Zhang, X, Nicoloso, MS, Rossi, S, Gonzalez-Villasana, V, Rupaimoole, R, Ferracin, M, Morabito, F, Neri, A, Ruvolo, PP, Ruvolo, VR, Pecot, CV, Amadori, D, Aruzzo, L, Calin, S, Wang, X, You, MJ, Ferrajoli, A, Orlowski, RZ, Plunkett, W, Lichtenberg, TM, Davuluri, RV, Berindan-Neagoe, I, Negrini, M, Wistuba, II, Hagop, K, Sood, AK, Lopez-Berestein, G, Keating, MJ, Fabbri, M & Calin, GA 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
Van Roosbroeck, Katrien ; Fanini, Francesca ; Setoyama, Tetsuro ; Ivan, Cristina ; Rodriguez-Aguayo, Cristian ; Fuentes-Mattei, Enrique ; Xiao, Lianchun ; Vannini, Ivan ; Redis, Roxana S. ; D'Abundo, Lucilla ; Zhang, Xinna ; Nicoloso, Milena S ; Rossi, Simona ; Gonzalez-Villasana, Vianey ; Rupaimoole, Rajesha ; Ferracin, Manuela ; Morabito, Fortunato ; Neri, Antonino ; Ruvolo, Peter P. ; Ruvolo, Vivian R ; Pecot, Chad V. ; Amadori, Dino ; Aruzzo, Lynne ; Calin, Steliana ; Wang, Xuemei ; You, Mingjian James ; Ferrajoli, Alessandra ; Orlowski, Robert Z. ; Plunkett, William ; Lichtenberg, Tara M. ; Davuluri, Ramana V. ; Berindan-Neagoe, Ioana ; Negrini, Massimo ; Wistuba, Ignacio I. ; Hagop, Kantarjian ; Sood, Anil K. ; Lopez-Berestein, Gabriel ; Keating, Michael J. ; Fabbri, Muller ; Calin, George A. / Combining anti-miR-155 with chemotherapy for the treatment of lung cancers. In: Clinical Cancer Research. 2016.
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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.",
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T1 - Combining anti-miR-155 with chemotherapy for the treatment of lung cancers

AU - Van Roosbroeck, Katrien

AU - Fanini, Francesca

AU - Setoyama, Tetsuro

AU - Ivan, Cristina

AU - Rodriguez-Aguayo, Cristian

AU - Fuentes-Mattei, Enrique

AU - Xiao, Lianchun

AU - Vannini, Ivan

AU - Redis, Roxana S.

AU - D'Abundo, Lucilla

AU - Zhang, Xinna

AU - Nicoloso, Milena S

AU - Rossi, Simona

AU - Gonzalez-Villasana, Vianey

AU - Rupaimoole, Rajesha

AU - Ferracin, Manuela

AU - Morabito, Fortunato

AU - Neri, Antonino

AU - Ruvolo, Peter P.

AU - Ruvolo, Vivian R

AU - Pecot, Chad V.

AU - Amadori, Dino

AU - Aruzzo, Lynne

AU - Calin, Steliana

AU - Wang, Xuemei

AU - You, Mingjian James

AU - Ferrajoli, Alessandra

AU - Orlowski, Robert Z.

AU - Plunkett, William

AU - Lichtenberg, Tara M.

AU - Davuluri, Ramana V.

AU - Berindan-Neagoe, Ioana

AU - Negrini, Massimo

AU - Wistuba, Ignacio I.

AU - Hagop, Kantarjian

AU - Sood, Anil K.

AU - Lopez-Berestein, Gabriel

AU - Keating, Michael J.

AU - Fabbri, Muller

AU - Calin, George A.

N1 - Copyright ©2016, American Association for Cancer Research.

PY - 2016/11/30

Y1 - 2016/11/30

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1158/1078-0432.CCR-16-1025

DO - 10.1158/1078-0432.CCR-16-1025

M3 - Article

C2 - 27903673

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

ER -