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Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms

Author

Listed:
  • Haijiao Zhang

    (Oregon Health & Science University Knight Cancer Institute
    Oregon Health & Science University Knight Cancer Institute)

  • Samantha Savage

    (Oregon Health & Science University Knight Cancer Institute
    Oregon Health & Science University Knight Cancer Institute)

  • Anna Reister Schultz

    (Oregon Health & Science University Knight Cancer Institute
    Oregon Health & Science University Knight Cancer Institute)

  • Daniel Bottomly

    (Oregon Health & Science University Knight Cancer Institute)

  • Libbey White

    (Oregon Health & Science University Knight Cancer Institute)

  • Erik Segerdell

    (Oregon Health & Science University Knight Cancer Institute)

  • Beth Wilmot

    (Oregon Health & Science University Knight Cancer Institute)

  • Shannon K. McWeeney

    (Oregon Health & Science University Knight Cancer Institute)

  • Christopher A. Eide

    (Oregon Health & Science University Knight Cancer Institute
    Howard Hughes Medical Institute)

  • Tamilla Nechiporuk

    (Oregon Health & Science University Knight Cancer Institute
    Oregon Health & Science University Knight Cancer Institute)

  • Amy Carlos

    (Oregon Health & Science University Knight Cancer Institute)

  • Rachel Henson

    (Oregon Health & Science University Knight Cancer Institute)

  • Chenwei Lin

    (Oregon Health & Science University Knight Cancer Institute)

  • Robert Searles

    (Oregon Health & Science University Knight Cancer Institute)

  • Hoang Ho

    (AROG Pharmaceuticals)

  • Yee Ling Lam

    (AROG Pharmaceuticals)

  • Richard Sweat

    (AROG Pharmaceuticals)

  • Courtney Follit

    (AROG Pharmaceuticals)

  • Vinay Jain

    (AROG Pharmaceuticals)

  • Evan Lind

    (Oregon Health & Science University Knight Cancer Institute)

  • Gautam Borthakur

    (The University of Texas MD Anderson Cancer Center)

  • Guillermo Garcia-Manero

    (The University of Texas MD Anderson Cancer Center)

  • Farhad Ravandi

    (The University of Texas MD Anderson Cancer Center)

  • Hagop M. Kantarjian

    (The University of Texas MD Anderson Cancer Center)

  • Jorge Cortes

    (The University of Texas MD Anderson Cancer Center)

  • Robert Collins

    (University of Texas Southwestern Medical Center)

  • Daelynn R. Buelow

    (The Ohio State University College of Pharmacy and Comprehensive Cancer Center)

  • Sharyn D. Baker

    (The Ohio State University College of Pharmacy and Comprehensive Cancer Center)

  • Brian J. Druker

    (Oregon Health & Science University Knight Cancer Institute
    Howard Hughes Medical Institute)

  • Jeffrey W. Tyner

    (Oregon Health & Science University Knight Cancer Institute
    Oregon Health & Science University Knight Cancer Institute)

Abstract

FLT3 mutations are prevalent in AML patients and confer poor prognosis. Crenolanib, a potent type I pan-FLT3 inhibitor, is effective against both internal tandem duplications and resistance-conferring tyrosine kinase domain mutations. While crenolanib monotherapy has demonstrated clinical benefit in heavily pretreated relapsed/refractory AML patients, responses are transient and relapse eventually occurs. Here, to investigate the mechanisms of crenolanib resistance, we perform whole exome sequencing of AML patient samples before and after crenolanib treatment. Unlike other FLT3 inhibitors, crenolanib does not induce FLT3 secondary mutations, and mutations of the FLT3 gatekeeper residue are infrequent. Instead, mutations of NRAS and IDH2 arise, mostly as FLT3-independent subclones, while TET2 and IDH1 predominantly co-occur with FLT3-mutant clones and are enriched in crenolanib poor-responders. The remaining patients exhibit post-crenolanib expansion of mutations associated with epigenetic regulators, transcription factors, and cohesion factors, suggesting diverse genetic/epigenetic mechanisms of crenolanib resistance. Drug combinations in experimental models restore crenolanib sensitivity.

Suggested Citation

  • Haijiao Zhang & Samantha Savage & Anna Reister Schultz & Daniel Bottomly & Libbey White & Erik Segerdell & Beth Wilmot & Shannon K. McWeeney & Christopher A. Eide & Tamilla Nechiporuk & Amy Carlos & R, 2019. "Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-018-08263-x
    DOI: 10.1038/s41467-018-08263-x
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    Cited by:

    1. Hanlin Wang & Guanghao Luo & Xiaobei Hu & Gaoya Xu & Tao Wang & Minmin Liu & Xiaohui Qiu & Jianan Li & Jingfeng Fu & Bo Feng & Yutong Tu & Weijuan Kan & Chang Wang & Ran Xu & Yubo Zhou & Jianmin Yang , 2023. "Targeting C/EBPα overcomes primary resistance and improves the efficacy of FLT3 inhibitors in acute myeloid leukaemia," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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