Overcoming adaptive therapy resistance in AML by targeting immune response pathways Journal Article

Authors: Melgar, K.; Walker, M. M.; Jones, L. M.; Bolanos, L. C.; Hueneman, K.; Wunderlich, M.; Jiang, J. K.; Wilson, K. M.; Zhang, X.; Sutter, P.; Wang, A.; Xu, X.; Choi, K.; Tawa, G.; Lorimer, D.; Abendroth, J.; O'Brien, E.; Hoyt, S. B.; Berman, E.; Famulare, C. A.; Mulloy, J. C.; Levine, R. L.; Perentesis, J. P.; Thomas, C. J.; Starczynowski, D. T.
Article Title: Overcoming adaptive therapy resistance in AML by targeting immune response pathways
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. © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
Journal Title: Science Translational Medicine
Volume: 11
Issue: 508
ISSN: 1946-6234
Publisher: American Association for the Advancement of Science  
Date Published: 2019-09-04
Start Page: aaw8828
Language: English
DOI: 10.1126/scitranslmed.aaw8828
PUBMED: 31484791
PROVIDER: scopus
PMCID: PMC6985905
Notes: Source: Scopus
Citation Impact
MSK Authors
  1. Ross Levine
    540 Levine
  2. Ellin Berman
    125 Berman