ArticleCancer cell2021
The AML microenvironment catalyzes a stepwise evolution to gilteritinib resistance.
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Article in Cancer cell, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 92 papers.
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92citing papers in PubMed
15.5field-weighted citation impact, top 1% of its field
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92 citing papers in PubMed, 144 citations in OpenAlex.
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32 more citing papers are in PubMed but not listed here.
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Authors and funding
32 authors at 4 institutions in 1 country.
Sunil K JoshiKnight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA; Department of Physiology & Pharmacology, School of Medicine, Oregon Health & Science University, Portland, OR, USA; Division of Hematology & Medical Oncology, Department of Medicine, Oregon Health & Science University, Portland, OR, USA.
Tamilla NechiporukKnight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA; Division of Hematology & Medical Oncology, Department of Medicine, Oregon Health & Science University, Portland, OR, USA.
Daniel BottomlyKnight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA; Division of Bioinformatics and Computational Biology, Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, OR, USA.
Paul D PiehowskiEnvironmental and Molecular Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA; Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.
Julie A ReiszDepartment of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Janét PittsenbargerKnight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA; Division of Hematology & Medical Oncology, Department of Medicine, Oregon Health & Science University, Portland, OR, USA.
Andy KaempfKnight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA; Biostatistics Shared Resource, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
Sara J C GoslineBiological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.
Yi-Ting WangBiological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.
Joshua R HansenBiological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.
Marina A GritsenkoBiological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.
Chelsea HutchinsonBiological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.
Karl K WeitzBiological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.
Jamie MoonBiological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.
Francesca CendaliDepartment of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Thomas L FillmoreEnvironmental and Molecular Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA; Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.
Chia-Feng TsaiBiological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.
Athena A SchepmoesBiological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.
Tujin ShiBiological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.
Osama A ArshadBiological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.
Jason E McDermottBiological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.
Ozgun BaburDepartment of Computer Science, University of Massachusetts, Boston, MA, USA.
Kevin Watanabe-SmithKnight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA; Computational Biology Program, Oregon Health & Science University, Portland, OR, USA.
Emek DemirKnight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA; Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA; Computational Biology Program, Oregon Health & Science University, Portland, OR, USA.
Angelo D'AlessandroDepartment of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Tao LiuBiological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.
Cristina E TognonKnight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA; Division of Hematology & Medical Oncology, Department of Medicine, Oregon Health & Science University, Portland, OR, USA.
Jeffrey W TynerKnight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA; Division of Hematology & Medical Oncology, Department of Medicine, Oregon Health & Science University, Portland, OR, USA; Department of Cell, Development, & Cancer Biology, Oregon Health & Science University, Portland, OR, USA.
Shannon K McWeeneyKnight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA; Division of Bioinformatics and Computational Biology, Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, OR, USA.
Karin D RodlandBiological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA; Department of Cell, Development, & Cancer Biology, Oregon Health & Science University, Portland, OR, USA.
Brian J DrukerKnight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA; Division of Hematology & Medical Oncology, Department of Medicine, Oregon Health & Science University, Portland, OR, USA; Department of Cell, Development, & Cancer Biology, Oregon Health & Science University, Portland, OR, USA.
Elie TraerKnight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA; Division of Hematology & Medical Oncology, Department of Medicine, Oregon Health & Science University, Portland, OR, USA; Department of Cell, Development, & Cancer Biology, Oregon Health & Science University, Portland, OR, USA. Electronic address: traere@ohsu.edu.
Pacific Northwest National Laboratory · USOregon Health & Science University · USUniversity of Colorado Anschutz Medical Campus · USUniversity of Massachusetts Boston · US
Funding
University of Colorado Cancer Center Support Grant - Lung Cancer Patient-Derived Xenografts with Autologous Human Immune SystemsP30CA046934 · NCI · UNIVERSITY OF COLORADO DENVER · PI James V Degregori · 1988 to 2026
$117.0MTumor Intrinsic and Microenvironmental Mechanisms Driving Drug Combination Efficacy and Resistance in AMLU54CA224019 · NCI · OREGON HEALTH & SCIENCE UNIVERSITY · PI Tothu Q Vu · 2017 to 2026
$13.9MProteogenomic Translational Research Center for Clinical ProteomicU01CA214116 · NCI · BATTELLE PACIFIC NORTHWEST LABORATORIES · PI DRUKER, BRIAN J, RODLAND, KARIN D · 2017 to 2021
$6.8MCenter for Advanced Multi-Omic Characterization of CancerU24CA271012 · NCI · BATTELLE PACIFIC NORTHWEST LABORATORIES · PI Tao Liu · 2022 to 2026
$6.6MPNNL Proteome Characterization CenterU24CA210955 · NCI · BATTELLE PACIFIC NORTHWEST LABORATORIES · PI LIU, TAO, SMITH, RICHARD D · 2016 to 2020
$5.3MFunctional Genomic Discovery of Pathway Targeted and Immune Modulatory Therapeutic Combinations in Hematologic MalignanciesU01CA217862 · NCI · OREGON HEALTH & SCIENCE UNIVERSITY · PI DRUKER, BRIAN J, TYNER, JEFFREY WALLACE · 2017 to 2021
$5.3MDefining the stromal landscape that sustains AML drug resistanceF30CA239335 · NCI · OREGON HEALTH & SCIENCE UNIVERSITY · PI JOSHI, SUNIL KUMAR · 2019 to 2022
$187kMechanisms of Drug Resistance in Acute Myeloid LeukemiaR50CA251708 · NCI · OREGON HEALTH & SCIENCE UNIVERSITY · PI NECHIPORUK, TAMILLA · 2020 to 2021
$174kNCI NIH HHS F30 CA239335NCI NIH HHS P30 CA046934NCI NIH HHS R50 CA251708NCI NIH HHS U01 CA214116NCI NIH HHS U01 CA217862NCI NIH HHS U24 CA210955NCI NIH HHS U24 CA271012NCI NIH HHS U54 CA224019
Abstract
Our study details the stepwise evolution of gilteritinib resistance in FLT3-mutated acute myeloid leukemia (AML). Early resistance is mediated by the bone marrow microenvironment, which protects residual leukemia cells. Over time, leukemia cells evolve intrinsic mechanisms of resistance, or late resistance. We mechanistically define both early and late resistance by integrating whole-exome sequencing, CRISPR-Cas9, metabolomics, proteomics, and pharmacologic approaches. Early resistant cells undergo metabolic reprogramming, grow more slowly, and are dependent upon Aurora kinase B (AURKB). Late resistant cells are characterized by expansion of pre-existing NRAS mutant subclones and continued metabolic reprogramming. Our model closely mirrors the timing and mutations of AML patients treated with gilteritinib. Pharmacological inhibition of AURKB resensitizes both early resistant cell cultures and primary leukemia cells from gilteritinib-treated AML patients. These findings support a combinatorial strategy to target early resistant AML cells with AURKB inhibitors and gilteritinib before the expansion of pre-existing resistance mutations occurs.
Indexed as
Drug Resistance, NeoplasmTumor MicroenvironmentAniline CompoundsAurora Kinase BBiomarkers, TumorExomeGene Expression Regulation, NeoplasticHumansLeukemia, Myeloid, AcuteMetabolomeProtein Kinase InhibitorsProteomePyrazinesTumor Cells, CulturedAniline CompoundsAURKB protein, humanAurora Kinase BBiomarkers, TumorgilteritinibProtein Kinase InhibitorsProteomePyrazinesAMLAurora kinase Bdrug resistanceFLT3gilteritiniblipid metabolismNRASquizartinibtumor microenvironmenttyrosine kinase inhibitor
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