Overcoming adaptive therapy resistance in AML by targeting immune response pathways
Katelyn Melgar1,2, Morgan M Walker3, LaQuita M Jones4
1Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
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.
Insights
Targeted therapies for acute myeloid leukemia (AML) often fail due to adaptive resistance. Researchers identified that inhibiting both FLT3 and IRAK1/4 kinases overcomes this resistance, offering a new treatment strategy for FLT3-mutant AML.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Targeted kinase inhibitors show early promise in acute myeloid leukemia (AML) but often lead to relapse due to adaptive resistance.
- Adaptive resistance involves target-dependent or target-independent mechanisms, including activation of survival pathways.
- FMS-like receptor tyrosine kinase (FLT3)-mutant AML is a significant subtype where understanding resistance is crucial.
Purpose of the Study:
- To elucidate mechanisms of adaptive resistance in FLT3-mutant AML following FLT3 inhibitor (FLT3i) treatment.
- To identify novel therapeutic strategies to overcome adaptive resistance in FLT3-mutant AML.
- To develop and evaluate a dual inhibitor targeting both FLT3 and the innate immune stress response pathway.
Main Methods:
- Integrative analysis of in-cell kinase and gene regulatory network responses in FLT3-mutant AML cells treated with FLT3i.
- Investigated the role of innate immune stress response pathways, specifically the interleukin-1 receptor-associated kinase 1 and 4 (IRAK1/4) complex.
- Developed and tested a novel small molecule inhibitor targeting both FLT3 and IRAK1/4 kinases in vitro and in vivo.
Main Results:
- FLT3 inhibitors induced activation of innate immune stress response pathways in FLT3-mutant AML cells.
- Activation of the IRAK1/4 complex was identified as a key contributor to adaptive resistance.
- The dual FLT3-IRAK1/4 inhibitor effectively eliminated adaptively resistant FLT3-mutant AML cells in preclinical models.
- The dual inhibitor demonstrated superior efficacy compared to existing FLT3-targeted therapies.
Conclusions:
- Innate immune pathway activation via IRAK1/4 is a critical mechanism of adaptive resistance in FLT3-mutant AML.
- Simultaneous inhibition of FLT3 and IRAK1/4 kinases represents a promising polypharmacologic strategy.
- This approach overcomes adaptive resistance and offers improved therapeutic efficacy for FLT3-mutant AML.
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