ArticleClinical cancer research : an official journal of the American Association for Cancer Research2024
Targeting CCL2/CCR2 Signaling Overcomes MEK Inhibitor Resistance in Acute Myeloid Leukemia.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
11 citing papers in PubMed, 16 citations in OpenAlex.
- Aging modulation of the immune system and immunotherapy efficacy in cancer.Frontiers in immunology · 2026Review
- Convergent Multistage Evidence Implicates the CCR2-Artemin Immune-Inflammation Axis in Acute Myeloid Leukemia.Mediators of inflammation · 2026Article
- Targeting TLK2 with antisense oligonucleotides as a new strategy in acute myeloid leukemia.Frontiers in oncology · 2026Article
- A microfluidic bone marrow model combining CFD and organ-on-a-chip technologies to study leukemia niche dynamics.Frontiers in bioengineering and biotechnology · 2026Article
- Lysosome-derived biomarkers for predicting survival outcome in acute myeloid leukemia.Discover oncology · 2025Article
- Targeting inflammation in cancer therapy: from mechanistic insights to emerging therapeutic approaches.Journal of translational medicine · 2025Review
- Targeting myeloid cells for hematological malignancies: the present and future.Biomarker research · 2025Review
- Quantitative Structure-Activity Relationship (QSAR) Modeling of Chiral CCR2 Antagonists with a Multidimensional Space of Novel Chirality Descriptors.Molecules (Basel, Switzerland) · 2025Article
- Epidemiology, molecular typing, microbiome-immune interactions and treatment strategies of endometrial cancer: a review.Frontiers in immunology · 2025Review
- Bone marrow immune cells and drug resistance in acute myeloid leukemia.Experimental biology and medicine (Maywood, N.J.) · 2025Review
- Mechanisms of resistance to tyrosine kinase inhibitor-targeted therapy and overcoming strategies.MedComm · 2024Review
Corrections and comments
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Authors and funding
21 authors at 4 institutions in 2 countries.
Funding
Abstract
purposeEmerging evidence underscores the critical role of extrinsic factors within the microenvironment in protecting leukemia cells from therapeutic interventions, driving disease progression, and promoting drug resistance in acute myeloid leukemia (AML). This finding emphasizes the need for the identification of targeted therapies that inhibit intrinsic and extrinsic signaling to overcome drug resistance in AML. EXPERIMENTAL
designWe performed a comprehensive analysis utilizing a cohort of ∼300 AML patient samples. This analysis encompassed the evaluation of secreted cytokines/growth factors, gene expression, and ex vivo drug sensitivity to small molecules. Our investigation pinpointed a notable association between elevated levels of CCL2 and diminished sensitivity to the MEK inhibitors (MEKi). We validated this association through loss-of-function and pharmacologic inhibition studies. Further, we deployed global phosphoproteomics and CRISPR/Cas9 screening to identify the mechanism of CCR2-mediated MEKi resistance in AML.
resultsOur multifaceted analysis unveiled that CCL2 activates multiple prosurvival pathways, including MAPK and cell-cycle regulation in MEKi-resistant cells. Employing combination strategies to simultaneously target these pathways heightened growth inhibition in AML cells. Both genetic and pharmacologic inhibition of CCR2 sensitized AML cells to trametinib, suppressing proliferation while enhancing apoptosis. These findings underscore a new role for CCL2 in MEKi resistance, offering combination therapies as an avenue to circumvent this resistance.
conclusionsOur study demonstrates a compelling rationale for translating CCL2/CCR2 axis inhibitors in combination with MEK pathway-targeting therapies, as a potent strategy for combating drug resistance in AML. This approach has the potential to enhance the efficacy of treatments to improve AML patient outcomes.
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Registered trials
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.