2. Academic Validation
  3. Overcoming adaptive therapy resistance in AML by targeting immune response pathways

Overcoming adaptive therapy resistance in AML by targeting immune response pathways

  • Sci Transl Med. 2019 Sep 4;11(508):eaaw8828. doi: 10.1126/scitranslmed.aaw8828.
Katelyn Melgar 1 2,  Morgan M Walker 3,  LaQuita M Jones 4,  Lyndsey C Bolanos 1,  Kathleen Hueneman 1,  Mark Wunderlich 1,  Jian-Kang Jiang 3,  Kelli M Wilson 3,  Xiaohu Zhang 3,  Patrick Sutter 3,  Amy Wang 3,  Xin Xu 3,  Kwangmin Choi 1,  Gregory Tawa 3,  Donald Lorimer 4,  Jan Abendroth 4,  Eric O'Brien 5,  Scott B Hoyt 3,  Ellin Berman 6,  Christopher A Famulare 7,  James C Mulloy 1,  Ross L Levine 6 7 8,  John P Perentesis 5,  Craig J Thomas 9 10,  Daniel T Starczynowski 11 12
Affiliations

Affiliations

  • 1 Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
  • 2 Immunology Graduate Program, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
  • 3 Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, USA.
  • 4 UCB Bainbridge, Bainbridge Island, WA 98110, USA.
  • 5 Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
  • 6 Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 7 Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 8 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 9 Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, USA. craigt@mail.nih.gov daniel.starczynowski@cchmc.org.
  • 10 Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20829, USA.
  • 11 Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. craigt@mail.nih.gov daniel.starczynowski@cchmc.org.
  • 12 Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
PMID: 31484791 DOI: 10.1126/scitranslmed.aaw8828
Abstract

Targeted inhibitors to oncogenic kinases demonstrate encouraging clinical responses early in the treatment course; however, most patients will relapse because of target-dependent mechanisms that mitigate enzyme-inhibitor binding or through target-independent mechanisms, such as alternate activation of survival and proliferation pathways, known as adaptive resistance. Here, we describe mechanisms of adaptive resistance in FMS-like receptor tyrosine kinase (FLT3)-mutant acute myeloid leukemia (AML) by examining integrative in-cell kinase and gene regulatory network responses after oncogenic signaling blockade by FLT3 inhibitors (FLT3i). We identified activation of innate immune stress response pathways after treatment of FLT3-mutant AML cells with FLT3i and showed that innate immune pathway activation via the interleukin-1 receptor-associated kinase 1 and 4 (IRAK1/4) complex contributes to adaptive resistance in FLT3-mutant AML cells. To overcome this adaptive resistance mechanism, we developed a small molecule that simultaneously inhibits FLT3 and IRAK1/4 kinases. The multikinase FLT3-IRAK1/4 inhibitor eliminated adaptively resistant FLT3-mutant AML cells in vitro and in vivo and displayed superior efficacy as compared to current targeted FLT3 therapies. These findings uncover a polypharmacologic strategy for overcoming adaptive resistance to therapy in AML by targeting immune stress response pathways.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-160787
    FLT3/IRAK1/4 Inhibitor