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

• Published in: PLoS computational biology Vol. 13; no. 7; p. e1005482
• Main Authors: Kaveh, Kamran, Takahashi, Yutaka, Farrar, Michael A, Storme, Guy, Guido, Marcucci, Piepenburg, Jamie, Penning, Jackson, Foo, Jasmine, Leder, Kevin Z, Hui, Susanta K
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.07.2017; Public Library of Science (PLoS)
• Subjects: Acute lymphoblastic leukemia; Acute lymphocytic leukemia; AKT protein; Animals; Apoptosis - drug effects; Apoptosis - radiation effects; Augmentation; Biology; Biology and Life Sciences; Cancer therapies; Cell death; Cell Line, Tumor; Chemoradiotherapy - methods; Chemotherapy; Chromosomes; Combination drug therapy; Computer applications; Computer Simulation; Dosage and administration; Drug dosages; Drug resistance; Drug Resistance, Neoplasm - radiation effects; Drug therapy; Enzyme inhibitors; Feasibility studies; Hematology; In vitro methods and tests; Leukemia; Lymphatic leukemia; Mathematical models; Medical prognosis; Medical research; Medicine; Medicine and Health Sciences; Mice; Models, Biological; Nilotinib; Observations; Oncology; Patient outcomes; Philadelphia chromosome; Physics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - physiopathology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - therapy; Protein-tyrosine kinase; Protein-Tyrosine Kinases - antagonists & inhibitors; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Pyrimidines - administration & dosage; Radiation; Radiotherapy; Research and Analysis Methods; Stem cells; Targeted cancer therapy; Therapy; Treatment Outcome; Tyrosine; United States > US; Minnesota; California
• ISSN: 1553-7358; 1553-734X; 1553-7358
• DOI: 10.1371/journal.pcbi.1005482

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.