Overcoming adaptive therapy resistance in AML by targeting immune response pathways.


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.


Melgar, Katelyn; Walker, Morgan M; Jones, LaQuita M; Bolanos, Lyndsey C; Hueneman, Kathleen; Wunderlich, Mark; Jiang, Jian-Kang; Wilson, Kelli; Zhang, Xiaohu; Sutter, Patrick; Wang, Amy; Xu, Xin; Choi, Kwangmin; Tawa, Gregory; Lorimer, Donald; Abendroth, Jan; O'Brien, Eric; Hoyt, Scott; Berman, Ellin; Famulare, Christopher A; Mulloy, James C; Levine, Ross L; Perentesis, John P; Thomas, Craig; Starczynowski, Daniel T;

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