ArticleScience translational medicine2019
Overcoming adaptive therapy resistance in AML by targeting immune response pathways.
Article in Science translational medicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers, 1 of them a synthesis that pooled it.
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Who cites it
57 citing papers in PubMed, 1 synthesis or guideline pooled it, 87 citations in OpenAlex.
- Acute Myeloid Leukemia: From Biology to Clinical Practices Through Development and Pre-Clinical Therapeutics.Frontiers in oncology · 2020Pooled it
- Inflammation as a central driver in AML pathogenesis and therapy resistance.Science China. Life sciences · 2026Review
- Review
- Dual-Targeting Strategy in Cancer Therapy: The Emerging Role of Pyrrolopyrimidine Scaffolds.Chemistry & biodiversity · 2026Review
- Potent and selective LSD1 inhibitor DC551040 reveals a promising combination therapy for AML with insight into epigenetic dysregulation.Signal transduction and targeted therapy · 2026Article
- Targeting IL-1/IRAK1/4 signaling in acute myeloid leukemia stem cells following treatment and relapse.Leukemia · 2026Article
- Recent Advances in FLT3-Based Dual Inhibitors: A Promising Strategy for the Treatment of Acute Myeloid Leukemia.Current medicinal chemistry · 2026Review
- Anti-inflammatory and Anti-arthritic Properties of Mucuna gigantea Plant Extracts: Establishing by Molecular Docking Study.Current computer-aided drug design · 2026Article
- IL-1 signaling and inflammasomes in acute myeloid leukemia: mechanisms and therapeutic opportunities.Cellular and molecular life sciences : CMLS · 2025Review
- Optimization of IRAK1/4/pan-FLT3 kinase inhibitors as treatments for acute myeloid leukemia.Bioorganic & medicinal chemistry letters · 2025Article
- Molecular Insights and Therapeutic Advances in Low-Risk Myelodysplastic Neoplasms: A Clinical Review.Cancers · 2025Review
- Meeting Report From the 2024 Symposium on IRAK4 in Cancer: Highlights and Clinical Updates.Clinical lymphoma, myeloma & leukemia · 2025Review
- Beyond diabetes: harnessing the power of metformin in burn care.Critical care (London, England) · 2025Review
- IRAK signaling in cancers: mechanisms, targeting, and clinical implications.Expert opinion on investigational drugs · 2025Review
- Targeting of IRAK4 and GSPT1 enhances therapeutic efficacy in AML via c-Myc destabilization.Leukemia · 2025Article
- Multi-omics integration reveals immune hallmarks and biomarkers associated with FLT3 inhibitor sensitivity in FLT3-mutated AML.Blood science (Baltimore, Md.) · 2025Article
- Ubiquitin-conjugating enzyme UBE2N modulates proteostasis in immunoproteasome-positive acute myeloid leukemia.The Journal of clinical investigation · 2025Article
- IRAK1/4/pan-FLT3 Kinase Inhibitors with Reduced hERG Block as Treatments for Acute Myeloid Leukemia.ACS medicinal chemistry letters · 2025Article
- Targeting rapid TKI-induced AXL upregulation overcomes adaptive ERK reactivation and exerts antileukemic effects in FLT3/ITD acute myeloid leukemia.Molecular oncology · 2025Article
- Low-risk MDS-A spotlight on precision medicine forHemaSphere · 2025Review
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25 authors at 4 institutions in 1 country.
Funding
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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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.