Combination therapeutics of Nilotinib and radiation in acute lymphoblastic leukemia as an effective method against drug-resistance

Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is characterized by a very poor prognosis and a high likelihood of acquired chemo-resistance. Although tyrosine kinase inhibitor (TKI) therapy has improved clinical outcome, most ALL patients relapse following treatment with TKI due to the development of resistance. We developed an in vitro model of Nilotinib-resistant Ph+ leukemia cells to investigate whether low dose radiation (LDR) in combination with TKI therapy overcome chemo-resistance. Additionally, we developed a mathematical model, parameterized by cell viability experiments under Nilotinib treatment and LDR, to explain the cellular response to combination therapy. The addition of LDR significantly reduced drug resistance both in vitro and in computational model. Decreased expression level of phosphorylated AKT suggests that the combination treatment plays an important role in overcoming resistance through the AKT pathway. Model-predicted cellular responses to the combined therapy provide good agreement with experimental results. Augmentation of LDR and Nilotinib therapy seems to be beneficial to control Ph+ leukemia resistance and the quantitative model can determine optimal dosing schedule to enhance the effectiveness of the combination therapy.Author summary: High likelihood of evolution of resistance to therapy is common in most forms of leukemia. This issue persists for tyrosine kinase inhibitor drug treatments as well as other forms of therapies. In the current work, we suggest a combination therapy where Ph+ acute lymphoblastic leukemic cells are treated with low-dose radiation before chemotherapy (Nilotinib). Our in vitro results of the combined therapy accompanied with a mathematical model shows successful suppression of resistance to Nilotinib. The mathematical model shows a synergistic interaction between Nilotinib and low dose radiation in the chemo dose response function. Beside acute radiation we investigate low dose fractionated therapies with model predicted optimal dosing schedules.