Research ArticleCancer

Overcoming adaptive therapy resistance in AML by targeting immune response pathways

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Science Translational Medicine  04 Sep 2019:
Vol. 11, Issue 508, eaaw8828
DOI: 10.1126/scitranslmed.aaw8828

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Killing two pathways with one inhibitor

Acute myeloid leukemia is an aggressive cancer that can be difficult to treat because of rapidly evolving therapeutic resistance. Melgar et al. focused on a subtype of acute myeloid leukemia characterized by mutations in a gene called FLT3. Although FLT3 inhibitors can target oncogenic signaling pathways in this cancer, their effects do not last. The authors identified a pathway involved in the innate immune stress response, whose activation promoted resistance to drugs targeting the FLT3 pathway, and then developed an inhibitor that targets both pathways at once. This multikinase inhibitor showed promising results in vitro and in animals, suggesting its potential for clinical translation.

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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