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A polypharmacologic strategy for overcoming adaptive therapy resistance in AML by targeting immune stress response pathways

Melgar, Katelyn M
http://orcid.org/0000-0001-7526-2265
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1571061798761171

Abstract Details

2019, PhD, University of Cincinnati, Medicine: Immunology.
Targeted inhibitors to oncogenic kinases demonstrate encouraging clinical responses early in the treatment course, however most patients will relapse due to 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 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 IRAK1/4 kinase complex contributes to adaptive resistance in FLT3-mutant AML cells. To overcome this acute adaptive resistance mechanism, we developed a small molecule that simultaneously inhibits FLT3 and IRAK1/4 kinases. The multi-kinase FLT3-IRAK1/4 inhibitor eliminated adaptively resistant FLT3-ITD 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.
Daniel Starczynowski, Ph.D. (Committee Chair)
H. Leighton Grimes, Ph.D. (Committee Member)
Ashish Kumar, M.D. (Committee Member)
Chandrashekhar Pasare (Committee Member)
William Seibel, Ph.D. (Committee Member)
140 p.
Oncology
Acute myeloid leukemia; FLT3; Innate immune signaling; IRAK4; adaptive resistance

Recommended Citations

Citations

  • Melgar, K. M. (2019). A polypharmacologic strategy for overcoming adaptive therapy resistance in AML by targeting immune stress response pathways [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1571061798761171

    APA Style (7th edition)

  • Melgar, Katelyn. A polypharmacologic strategy for overcoming adaptive therapy resistance in AML by targeting immune stress response pathways. 2019. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1571061798761171.

    MLA Style (8th edition)

  • Melgar, Katelyn. "A polypharmacologic strategy for overcoming adaptive therapy resistance in AML by targeting immune stress response pathways." Doctoral dissertation, University of Cincinnati, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1571061798761171

    Chicago Manual of Style (17th edition)

ucin1571061798761171
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© 2019, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.