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

doi:10.1182/blood-2016-04-711820

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

73 Scopus citations

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 language	English (US)
Pages (from-to)	48-58
Number of pages	11
Journal	Blood
Volume	130
Issue number	1
DOIs	https://doi.org/10.1182/blood-2016-04-711820
State	Published - Jul 6 2017

ASJC Scopus subject areas

Biochemistry
Immunology
Hematology
Cell Biology

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10.1182/blood-2016-04-711820

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Smith, C. C., Paguirigan, A., Jeschke, G. R., Lin, K. C., Massi, E., Tarver, T., Chin, C. S., Asthana, S., Olshen, A., Travers, K. J., Wang, S., Levis, M. J., Perl, A. E., Radich, J. P., & 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

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title = "Heterogeneous resistance to quizartinib in acute myeloid leukemia revealed by single-cell analysis",

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.",

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

note = "Funding Information: This work was supported in part by grants 1RO1 CA176091 (N.P.S.), 5P30CA82103 (A.O.), K08 CA187577 (C.C.S.), R01 CA149566 (A.P. and J.P.R.), R01 CA1752515 (A.P. and J.P.R.), and R01 CA175008 (A.P., and J.P.R.), and Specialized Programs of Research Excellence grant P50 CA 100632 (M.J.L.) from the National Institutes of Health, National Cancer Institute, and by the Edward S. Ageno Foundation (N.P.S.). CCS. is an American Society of Hematology faculty scholar and recipient of a Hellman Family Foundation Early Career Faculty Award.",

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AU - Jeschke, Grace R.

AU - Lin, Kimberly C.

AU - Massi, Evan

AU - Tarver, Theodore

AU - Chin, Chen Shan

AU - Asthana, Saurabh

AU - Olshen, Adam

AU - Travers, Kevin J.

AU - Wang, Susana

AU - Levis, Mark J.

AU - Perl, Alexander E.

AU - Radich, Jerald P.

AU - Shah, Neil P.

N1 - Funding Information: This work was supported in part by grants 1RO1 CA176091 (N.P.S.), 5P30CA82103 (A.O.), K08 CA187577 (C.C.S.), R01 CA149566 (A.P. and J.P.R.), R01 CA1752515 (A.P. and J.P.R.), and R01 CA175008 (A.P., and J.P.R.), and Specialized Programs of Research Excellence grant P50 CA 100632 (M.J.L.) from the National Institutes of Health, National Cancer Institute, and by the Edward S. Ageno Foundation (N.P.S.). CCS. is an American Society of Hematology faculty scholar and recipient of a Hellman Family Foundation Early Career Faculty Award.

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

Abstract

ASJC Scopus subject areas

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