RESUMEN
Finding synergistic drug combinations is an important area of cancer research. Here, we sought to rationally design synergistic drug combinations with an inhibitor of BTK kinase, ibrutinib, which is used for the treatment of several types of leukemia. We (a) used a pooled shRNA screen to identify genes that protect cells from the drug, (b) identified protective pathways via bioinformatics analysis of these gene sets, and (c) identified drugs that inhibit these pathways. Based on this analysis, we established that inhibitors of proteasome and mTORC1 could synergize with ibrutinib both in vitro and in vivo. We suggest that FDA-approved inhibitors of these pathways could be effectively combined with ibrutinib for the treatment of chronic lymphocytic leukemia (CLL).
Asunto(s)
Leucemia Linfocítica Crónica de Células B , Humanos , Leucemia Linfocítica Crónica de Células B/metabolismo , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Pirazoles/farmacología , Pirazoles/uso terapéutico , Combinación de Medicamentos , ARN Interferente Pequeño/genéticaRESUMEN
In recent years, mathematical models have developed into an important tool for cancer research, combining quantitative analysis and natural processes. We have focused on Chronic Lymphocytic Leukemia (CLL), since it is one of the most common adult leukemias, which remains incurable. As the first step toward the mathematical prediction of in vivo drug efficacy, we first found that logistic growth best described the proliferation of fluorescently labeled murine A20 leukemic cells injected in immunocompetent Balb/c mice. Then, we tested the cytotoxic efficacy of Ibrutinib (Ibr) and Cytarabine (Cyt) in A20-bearing mice. The results afforded calculation of the killing rate of the A20 cells as a function of therapy. The experimental data were compared with the simulation model to validate the latter's applicability. On the basis of these results, we developed a new ordinary differential equations (ODEs) model and provided its sensitivity and stability analysis. There was excellent accordance between numerical simulations of the model and results from in vivo experiments. We found that simulations of our model could predict that the combination of Cyt and Ibr would lead to approximately 95% killing of A20 cells. In its current format, the model can be used as a tool for mathematical prediction of in vivo drug efficacy, and could form the basis of software for prediction of personalized chemotherapy.