Fitness conferred by BCR-ABL kinase domain mutations determines the risk of pre-existing resistance in chronic myeloid leukemia.

摘要: Chronic myeloid leukemia (CML) is the first human malignancy to be successfully treated with a small molecule inhibitor, imatinib, targeting mutant oncoprotein (BCR-ABL). Despite its successes, acquired resistance imatinib leads reduced drug efficacy and frequent progression of disease. Understanding characteristics pre-existing resistant cells important for evaluating benefits first-line combination therapy second generation inhibitors. However, due limitations assay sensitivity, determining existence cell clones at start difficult. Here we combined mathematical modeling approach using branching processes experimental data on fitness changes (i.e., in net reproductive rate) conferred by BCR-ABL kinase domain mutations investigate likelihood, composition, diversity resistance. Furthermore, studied impact these factors response tyrosine Our predicts that most patients, there one clone present time diagnosis their Interestingly, patients are no more likely harbor aggressive, pan-resistant T315I mutation than any other mutation; however, average establish larger-sized diagnosis. We established diagnosed late, relative benefit over monotherapy significant, while this modest typically early time. These findings, after pre-clinical validation, will have implications clinical management CML: recommend advanced-phase disease least two