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

被引：145

作者：

Smith, Catherine C. ^{[1
,2
]}

Paguirigan, Amy ^{[3
]}

Jeschke, Grace R. ^{[4
]}

Lin, Kimberly C. ^{[1
]}

Massi, Evan ^{[1
]}

Tarver, Theodore ^{[1
]}

Chin, Chen-Shan ^{[5
]}

Asthana, Saurabh ^{[2
]}

Olshen, Adam ^{[2
,6
]}

Travers, Kevin J. ^{[5
,8
]}

Wang, Susana ^{[5
]}

Levis, Mark J. ^{[7
]}

Perl, Alexander E. ^{[4
]}

Radich, Jerald P. ^{[3
]}

Shah, Neil P. ^{[1
,2
]}

机构：

[1] Univ Calif San Francisco, Div Hematol Oncol, San Francisco, CA 94143 USA

[2] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA

[3] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA

[4] Univ Penn, Div Hematol Oncol, Abramson Canc Ctr, Philadelphia, PA 19104 USA

[5] Pacific Biosci, Menlo Pk, CA USA

[6] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA

[7] Johns Hopkins Univ, Dept Oncol, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA

[8] Roche Sequencing Solut, Santa Clara, CA USA

来源：

BLOOD | 2017年 / 130卷 / 01期

基金：

美国国家卫生研究院;

关键词：

THERAPEUTIC TARGET; CLONAL EVOLUTION; F691L MUTATION; FLT3; SORAFENIB; INHIBITION; MECHANISMS; EMERGENCE; CANCER; D835;

D O I：

10.1182/blood-2016-04-711820

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：48 / 58

页数：11

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