Systems biology drug screening identifies statins as enhancers of current therapies in chronic lymphocytic leukemia

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• dc.contributor.author Gimenez, Neus
• dc.contributor.author Tripathi, Rupal
• dc.contributor.author Giró, Ariadna
• dc.contributor.author Rosich, Laia
• dc.contributor.author López-Guerra, Mónica
• dc.contributor.author López-Oreja, Irene
• dc.contributor.author Playa-Albinyana, Heribert
• dc.contributor.author Arenas, Fabián
• dc.contributor.author Mas, José Manuel
• dc.contributor.author Pérez-Galán, Patricia
• dc.contributor.author Delgado González, Julio
• dc.contributor.author Campo, Elias
• dc.contributor.author Farrés, Judith
• dc.contributor.author Colomer Pujol, Dolors
• dc.date.accessioned 2022-06-14T09:05:28Z
• dc.date.available 2022-06-14T09:05:28Z
• dc.date.issued 2020
• dc.description.abstract Chronic lymphocytic leukemia (CLL) is a B lymphoid malignancy highly dependent on the microenvironment. Despite new targeted therapies such as ibrutinib and venetoclax, disease progression and relapse remain an issue. CLL cell interactions with the supportive tissue microenvironment play a critical role in disease pathogenesis. We used a platform for drug discovery based on systems biology and artificial intelligence, to identify drugs targeting key proteins described to have a role in the microenvironment. The selected compounds were screened in CLL cell lines in the presence of stromal cells to mimic the microenvironment and validated the best candidates in primary CLL cells. Our results showed that the commercial drug simvastatin was the most effective and selective out of the tested compounds. Simvastatin decreased CLL cell survival and proliferation as well as cell adhesion. Importantly, this drug enhanced the antitumor effect of venetoclax and ibrutinib. We proposed that systems biology approaches combined with pharmacological screening could help to find new drugs for CLL treatment and to predict new combinations with current therapies. Our results highlight the possibility of repurposing widely used drugs such as statins to target the microenvironment and to improve the efficacy of ibrutinib or venetoclax in CLL cells.
• dc.description.sponsorship The study was supported by research funding from the Spanish Ministry of Economy and Competitiveness through the Plan Estatal de Investigación Científica y Técnica y de Innovación (MINECO) RTI2018-094584-B-I00 [to DC] and was cofunded by the European Regional Development Fund [ERDF] and the CERCA program from Generalitat de Catalunya, Centro de Investigación Biomédica en Cáncer [CIBERONC] [CB16/12/00334 and CB16/12/00225] and Generalitat de Catalunya Suport Grups de Recerca [2017 SGR 1009]. This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 306240. NG is a recipient of a predoctoral fellowship from AGAUR, L.R. is a recipient of a postdoctoral fellowship from AGAUR (PERIS), ILO is a recipient of the PhD4MD program and HPA is a recipient of a predoctiral fellowship from Spanish Ministry of Economy and Competitiveness (FPU)
• dc.format.mimetype application/pdf
• dc.identifier.citation Gimenez N, Tripathi R, Giró A, Rosich L, López-Guerra M, López-Oreja I et al. Systems biology drug screening identifies statins as enhancers of current therapies in chronic lymphocytic leukemia. Sci Rep. 2020 Dec 17;10(1):22153. DOI:10.1038/s41598-020-78315-0
• dc.identifier.doi http://dx.doi.org/10.1038/s41598-020-78315-0
• dc.identifier.issn 2045-2322
• dc.identifier.uri http://hdl.handle.net/10230/53488
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/306240
• dc.rights © Neus Gimenez et al 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri https://creativecommons.org/licenses/by/4.0/
• dc.subject.other Leucèmia limfocítica crònica
• dc.subject.other Genètica
• dc.subject.other Medicaments -- Anàlisi
• dc.title Systems biology drug screening identifies statins as enhancers of current therapies in chronic lymphocytic leukemia
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion