Cited by 447Acute Myeloid Leukemia ResearchCancer Genomics and DiagnosticsChronic Myeloid Leukemia Treatments

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Clonal Selection with RAS Pathway Activation Mediates Secondary Clinical Resistance to Selective FLT3 Inhibition in Acute Myeloid Leukemia

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McMahon, Christine M., Ferng, Timothy, Canaani, Jonathan, Wang, Eunice S., Morrissette, Jennifer J.D., Eastburn, Dennis J., Pellegrino, Maurizio, Durruthy-Durruthy, Robert, Watt, Christopher D., Asthana, Saurabh, Lasater, Elisabeth A., DeFilippis, RosaAnna, Peretz, Cheryl A.C., McGary, Lisa H.F., Deihimi, Safoora, Logan, Aaron C., Luger, Selina M., Shah, Neil P., Carroll, Martin, Smith, Catherine C., Perl, Alexander E.·2019·Cancer Discovery

DOI 10.1158/2159-8290.cd-18-1453PMC PMC11994087

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Abstract

Gilteritinib is a potent and selective FLT3 kinase inhibitor with single-agent clinical efficacy in relapsed/refractory FLT3-mutated acute myeloid leukemia (AML). In this context, however, gilteritinib is not curative, and response duration is limited by the development of secondary resistance. To evaluate resistance mechanisms, we analyzed baseline and progression samples from patients treated on clinical trials of gilteritinib. Targeted next-generation sequencing at the time of AML progression on gilteritinib identified treatment-emergent mutations that activate RAS/MAPK pathway signaling, most commonly in NRAS or KRAS. Less frequently, secondary FLT3-F691L gatekeeper mutations or BCR–ABL1 fusions were identified at progression. Single-cell targeted DNA sequencing revealed diverse patterns of clonal selection and evolution in response to FLT3 inhibition, including the emergence of RAS mutations in FLT3-mutated subclones, the expansion of alternative wild-type FLT3 subclones, or both patterns simultaneously. These data illustrate dynamic and complex changes in clonal architecture underlying response and resistance to mutation-selective tyrosine kinase inhibitor therapy in AML. Significance: Comprehensive serial genotyping of AML specimens from patients treated with the selective FLT3 inhibitor gilteritinib demonstrates that complex, heterogeneous patterns of clonal selection and evolution mediate clinical resistance to tyrosine kinase inhibition in FLT3-mutated AML. Our data support the development of combinatorial targeted therapeutic approaches for advanced AML. See related commentary by Wei and Roberts, p. 998. This article is highlighted in the In This Issue feature, p. 983

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Cortes, 2018, Quizartinib significantly prolongs overall survival in patients with FLT3-internal tandem duplication–mutated relapsed/refractory AML in the phase 3, randomized, controlled QuANTUM-R trial [abstract]

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Authors: McMahon, C. M., Ferng, T., Canaani, J., Wang, E. S., Morrissette, J. J. D., Eastburn, D. J., Pellegrino, M., Durruthy-Durruthy, R., Watt, C. D., Asthana, S., Lasater, E. A., DeFilippis, R., Peretz, C. A. C., McGary, L. H. F., Deihimi, S., Logan, A. C., Luger, S. M., Shah, N. P., Carroll, M., Smith, C. C., & Perl, A. E.
Affiliations: University of Pennsylvania (US)
University of California, San Francisco (US)
Tel Aviv University (IL)
Roswell Park Comprehensive Cancer Center (US)
Mission Bio (United States) (US)
United States Department of Veterans Affairs (US)
ORCID: McMahon, Christine M.
Ferng, Timothy
Canaani, Jonathan
Wang, Eunice S.
Morrissette, Jennifer J.D.
Eastburn, Dennis J.
Pellegrino, Maurizio
DeFilippis, RosaAnna
Peretz, Cheryl A.C.
McGary, Lisa H.F.
Logan, Aaron C.
Luger, Selina M.
Shah, Neil P.
Carroll, Martin
Smith, Catherine C.
Perl, Alexander E.
Venue: Cancer Discovery
Publisher: American Association for Cancer Research (AACR)
Published: 2019-08-01
Volume: 9
Issue: 8
Pages: 1050-1063
ISSN: 2159-8274 (ISSN-L)
2159-8290
DOI: 10.1158/2159-8290.cd-18-1453
PMC: PMC11994087
OpenAlex: W2946259536
Cited by: 446
References: 35
Citations by year: 2026: 35 · 2025: 55 · 2024: 56 · 2023: 62 · 2022: 91 · 2021: 61 · 2020: 68 · 2019: 16
FWCI: 41.51
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Cancer Discovery (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: HHS | NIH | National Center for Advancing Translational SciencesHHS | NIH | National Center for Advancing Translational Sciences (NCATS) (TL1TR001880)
American Society of Clinical OncologyAmerican Society of Clinical Oncology (ASCO)
HHS | NIH | National Cancer InstituteHHS | NIH | National Cancer Institute (NCI) (R21 CA198621, R01 CA198089, R01 CA166616, K08 CA187577)
Damon Runyon Cancer Research FoundationDamon Runyon Cancer Research Foundation (Damon Runyon) (CI-99-18)
Biff Ruttenberg Foundation
Topics: Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
Keywords: acute myeloid leukemia, FLT3 mutation, gilteritinib, FLT3 inhibitor resistance, clonal selection, clonal evolution, NRAS mutation, KRAS mutation, BCR-ABL fusion gene, tyrosine kinase inhibitor resistance, single-cell DNA sequencing
MeSH terms: Adult, Aged, Aged, 80 and over, Aniline Compounds, Female, Humans, Male, Middle Aged, Mutation, Pyrazines, Signal Transduction, Leukemia, Myeloid, Acute, ras Proteins, Drug Resistance, Neoplasm, Protein Kinase Inhibitors, fms-Like Tyrosine Kinase 3, Young Adult, Single-Cell Analysis, High-Throughput Nucleotide Sequencing, Clonal Evolution

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Clonal Selection with RAS Pathway Activation Mediates Secondary Clinical Resistance to Selective FLT3 Inhibition in Acute Myeloid Leukemia

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