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
  • 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. [email protected] [email protected].
  • 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. [email protected] [email protected].
  • 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.

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