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Blood. 2017 Jul 6;130(1):48-58. doi: 10.1182/blood-2016-04-711820. Epub 2017 May 10.

Heterogeneous resistance to quizartinib in acute myeloid leukemia revealed by single-cell analysis.

Author information

1
Division of Hematology/Oncology and.
2
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA.
3
Fred Hutchinson Cancer Research Center, Seattle, WA.
4
Division of Hematology/Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA.
5
Pacific Biosciences, Menlo Park, CA.
6
Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA; and.
7
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD.

Abstract

Genomic studies have revealed significant branching heterogeneity in cancer. Studies of resistance to tyrosine kinase inhibitor therapy have not fully reflected this heterogeneity because resistance in individual patients has been ascribed to largely mutually exclusive on-target or off-target mechanisms in which tumors either retain dependency on the target oncogene or subvert it through a parallel pathway. Using targeted sequencing from single cells and colonies from patient samples, we demonstrate tremendous clonal diversity in the majority of acute myeloid leukemia (AML) patients with activating FLT3 internal tandem duplication mutations at the time of acquired resistance to the FLT3 inhibitor quizartinib. These findings establish that clinical resistance to quizartinib is highly complex and reflects the underlying clonal heterogeneity of AML.

PMID:
28490572
PMCID:
PMC5501146
DOI:
10.1182/blood-2016-04-711820
[Indexed for MEDLINE]
Free PMC Article

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