High-throughput drug repurposing for precision medicine in the treatment of leukaemia in South African patients

Abstract

Leukaemia, a heterogeneous group of haematological malignancies, presents significant challenges in diagnosis, treatment, and management, particularly in resource-constrained regions such as South Africa. Despite advancements in targeted therapies, drug resistance remains a major obstacle in leukaemia treatment, necessitating the exploration of alternative therapeutic approaches. Drug repurposing, which involves identifying new indications for existing drugs, offers a cost-effective and time-efficient strategy to expand treatment options. However, there is limited research on how leukaemia patients in South Africa respond to potential repurposed drugs and combination therapies. To address these gaps, forty-one leukaemia patients, including AML, CML, and CLL, were recruited, and their demographic, clinical, and treatment history profiles were analysed. Drug sensitivity screening was performed using 30 FDA-approved drugs on peripheral blood mononuclear cells (PBMCs) isolated from these patients. The effect of the ten promising single drug candidates and their combinations was further evaluated on cell viability and CD markers like CD3, CD8, CD19, CD38, and HLA-DR via multicolour flow cytometry, providing insights into the cell death mode, immune cell dynamics, disease progression, and treatment response. Finally, the molecular docking of irinotecan and nilotinib with proteins involved in key leukaemia signalling pathways was performed to evaluate the binding affinity. The result provided valuable insights into the disparities in the demographic, clinical, treatment history, and molecular landscape of South African leukaemia patients, highlighting the variability in drug responses among patients with different treatment histories. Irinotecan was found to be the most potent drug, with an average DSS score of 9.5. Among the three drug combinations tested, the combination of irinotecan with nilotinib was found to be the best, with a Loewe synergy score of -10.61. The flow cytometry results showed a moderate increase or activation of CD3+ cells (16.7%) upon treatment with irinotecan and nilotinib compared to the untreated condition (10.5%). Within the CD3+ population, patient cells treated with irinotecan and nilotinib showed a slight decrease in CD3+CD8- cells and an increase in CD3+CD8+ (24.9% vs 28.7% respectively) compared to the control sample. The molecular docking results demonstrated that irinotecan and nilotinib could act by inhibiting mTOR and PI3K by interacting with the amino acids at their docking sites through various covalent and non-covalent interactions. In the context of drug repurposing for the treatment of leukaemia in South Africa, this research contributes to personalized medicine approaches by showing the feasibility of drug screening to identify potential drug candidates for patients who have exhausted treatment options.