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 |
| DOI/URL: | |
| Notes: | Source: Scopus |
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