Single-molecule sequencing reveals patterns of pre-existing drug resistance that suggest treatment strategies in Philadelphia-positive leukemias
| Autor: | Bella I. Aminov, Victor M. Rivera, Justin R. Pritchard, Lawrence A. Loeb, Jerald P. Radich, Lan Beppu, Daniel S. Kim, Scott M. Leighow, Michael W. Schmitt, J. Graeme Hodgson |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research medicine.medical_treatment DNA Mutational Analysis Drug resistance Philadelphia chromosome Somatic evolution in cancer Article Targeted therapy Clonal Evolution 03 medical and health sciences Genetic Heterogeneity 0302 clinical medicine hemic and lymphatic diseases Cell Line Tumor Leukemia Myelogenous Chronic BCR-ABL Positive medicine Humans Philadelphia Chromosome ABL Leukemia Genetic heterogeneity business.industry Myeloid leukemia High-Throughput Nucleotide Sequencing Sequence Analysis DNA Precursor Cell Lymphoblastic Leukemia-Lymphoma medicine.disease Prognosis 030104 developmental biology Oncology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Mutation Cancer research business |
| Popis: | Purpose: Sequential treatment with targeted therapies can result in complex combinations of resistance mutations in drug targets. This mutational complexity has spurred the development of pan-target inhibitors, i.e., therapies for which no single target mutation can cause resistance. Because the propensity for on- versus off-target resistance varies across cancer types, a deeper understanding of the mutational burden in drug targets could rationalize treatment outcomes and prioritize pan-target inhibitors for indications where on-target mutations are most likely. Experimental Design: To measure and model the mutational landscape of a drug target at high resolution, we integrated single-molecule Duplex Sequencing of the ABL1 gene in Philadelphia-positive (Ph+) leukemias with computational simulations. Results: A combination of drug target mutational burden and tumor-initiating cell fraction is sufficient to predict that most patients with chronic myeloid leukemia are unlikely to harbor ABL1 resistance mutations at the time of diagnosis, rationalizing the exceptional success of targeted therapy in this setting. In contrast, our analysis predicts that many patients with Ph+ acute lymphoblastic leukemia (Ph+ ALL) harbor multiple preexisting resistant cells with single mutants. The emergence of compound mutations can be traced to initial use of an ABL1 inhibitor that is susceptible to resistance from single point mutations. Conclusions: These results argue that early use of therapies that achieve pan-inhibition of ABL1 resistance mutants might improve outcomes in Ph+ ALL. Our findings show how a deep understanding of the mutational burden in drug targets can be quantitatively coupled to phenotypic heterogeneity to rationalize clinical phenomena. Clin Cancer Res; 24(21); 5321–34. ©2018 AACR. |
| Databáze: | OpenAIRE |
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