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Clonal Selection with RAS Pathway Activation Mediates Secondary Clinical Resistance to Selective FLT3 Inhibition in Acute Myeloid Leukemia
Open accessPublished version of a preprint
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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“However, clinical response duration to FLT3 inhibitor treatment remains short partially due to the development of secondary resistance [130].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [130]
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Metadata
- 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
- Venue
- Cancer Discovery
- Published
- 2019-08-01
- Volume
- 9
- Issue
- 8
- Pages
- 1050-1063
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- 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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