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

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.

• Authors: Neus Gimenez, Rupal Tripathi, Ariadna Giró, Laia Rosich, Mònica López-Guerra, Irene López-Oreja, Heribert Playa-Albinyana, Fabian Arenas, José Manuel Mas, Patricia Pérez-Galán, Julio Delgado, Elias Campo, Judith Farrés, Dolors Colomer
• Journal: Scientific reports (Sci Rep) Vol. 10 Issue 1 Pg. 22153 (12 17 2020) ISSN: 2045-2322 [Electronic] England
• PMID: 33335123 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Biomarkers
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Small Molecule Libraries

Topics

• Antineoplastic Agents (chemistry, pharmacology, therapeutic use)
• Biomarkers
• Cell Proliferation
• Cell Survival (drug effects)
• Drug Evaluation, Preclinical (methods)
• Drug Screening Assays, Antitumor (methods)
• Drug Synergism
• Gene Expression Regulation, Leukemic (drug effects)
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (chemistry, pharmacology, therapeutic use)
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy, etiology, metabolism)
• Models, Molecular
• Reproducibility of Results
• Signal Transduction (drug effects)
• Small Molecule Libraries
• Structure-Activity Relationship
• Systems Biology (methods)
• Tumor Microenvironment (drug effects)