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Heterogeneous resistance to quizartinib in acute myeloid leukemia (AML) 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 and Neil P. Shah

Key points

  • Demonstrated by single cell analysis, polyclonal mechanisms of resistance occur in the majority of AML patients who relapse on quizartinib.

Abstract

Genomic studies have revealed significant branching heterogeneity in cancer. Studies of resistance to tyrosine kinase inhibitor (TKI) therapy have not fully reflected this heterogeneity as 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 (ITD) 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.

  • Submitted April 22, 2016.
  • Accepted May 3, 2017.