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

Catherine C. Smith, Amy Paguirigan, Grace R. Jeschke, Kimberly C. Lin, Evan Massi, Theodore Tarver, Chen Shan Chin, Saurabh Asthana, Adam Olshen, Kevin J. Travers, Susana Wang, Mark J Levis, Alexander E. Perl, Jerald P. Radich, Neil P. Shah

Research output: Contribution to journalArticle

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 oncogeneorsubvert 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.

Original languageEnglish (US)
Pages (from-to)48-58
Number of pages11
JournalBlood
Volume130
Issue number1
DOIs
StatePublished - Jul 6 2017

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Single-Cell Analysis
Acute Myeloid Leukemia
Protein-Tyrosine Kinases
Tumors
Neoplasms
Mutation
quizartinib
Therapeutics

ASJC Scopus subject areas

  • Immunology
  • Biochemistry
  • Hematology
  • Cell Biology

Cite this

Smith, C. C., Paguirigan, A., Jeschke, G. R., Lin, K. C., Massi, E., Tarver, T., ... Shah, N. P. (2017). Heterogeneous resistance to quizartinib in acute myeloid leukemia revealed by single-cell analysis. Blood, 130(1), 48-58. https://doi.org/10.1182/blood-2016-04-711820

Heterogeneous resistance to quizartinib in acute myeloid leukemia revealed by single-cell analysis. / Smith, Catherine C.; Paguirigan, Amy; Jeschke, Grace R.; Lin, Kimberly C.; Massi, Evan; Tarver, Theodore; Chin, Chen Shan; Asthana, Saurabh; Olshen, Adam; Travers, Kevin J.; Wang, Susana; Levis, Mark J; Perl, Alexander E.; Radich, Jerald P.; Shah, Neil P.

In: Blood, Vol. 130, No. 1, 06.07.2017, p. 48-58.

Research output: Contribution to journalArticle

Smith, CC, Paguirigan, A, Jeschke, GR, Lin, KC, Massi, E, Tarver, T, Chin, CS, Asthana, S, Olshen, A, Travers, KJ, Wang, S, Levis, MJ, Perl, AE, Radich, JP & Shah, NP 2017, 'Heterogeneous resistance to quizartinib in acute myeloid leukemia revealed by single-cell analysis', Blood, vol. 130, no. 1, pp. 48-58. https://doi.org/10.1182/blood-2016-04-711820
Smith CC, Paguirigan A, Jeschke GR, Lin KC, Massi E, Tarver T et al. Heterogeneous resistance to quizartinib in acute myeloid leukemia revealed by single-cell analysis. Blood. 2017 Jul 6;130(1):48-58. https://doi.org/10.1182/blood-2016-04-711820
Smith, Catherine C. ; Paguirigan, Amy ; Jeschke, Grace R. ; Lin, Kimberly C. ; Massi, Evan ; Tarver, Theodore ; Chin, Chen Shan ; Asthana, Saurabh ; Olshen, Adam ; Travers, Kevin J. ; Wang, Susana ; Levis, Mark J ; Perl, Alexander E. ; Radich, Jerald P. ; Shah, Neil P. / Heterogeneous resistance to quizartinib in acute myeloid leukemia revealed by single-cell analysis. In: Blood. 2017 ; Vol. 130, No. 1. pp. 48-58.
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