ArticleScience translational medicine2014
A therapeutically targetable mechanism of BCR-ABL-independent imatinib resistance in chronic myeloid leukemia.
Article in Science translational medicine, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 80 papers.
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Who cites it
80 citing papers in PubMed, 133 citations in OpenAlex.
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- Reduced levels of ITGB1 cause activation of p38MAPK-ERK-LYN axis of BCR::ABL1 signaling despite inactivation of the oncoprotein by imatinib - novel resistance mechanism in blast crisis of chronic myeloid leukemia unraveled.Cell communication and signaling : CCS · 2026Article
- Directed evolution-based discovery of ligands for in vivo restimulation of chimeric antigen receptor T cells.Nature biomedical engineering · 2026Article
- Data Mining for Identification of Targets and Repurposed Drugs to Eliminate Persistent Chronic Myeloid Leukaemia Stem Cells: Targeting RAS/RAF Signalling.Oncology research · 2026Article
- Integrin-linked kinase (ILK) in hematologic malignancies: Bridging molecular mechanisms to therapeutic innovation.BioImpacts : BI · 2026Review
- SUMOylation facilitates the stability of BCR-ABL to promote chronic myeloid leukemia progression.Oncogene · 2025Article
- CDK8/19 inhibition attenuates G1 arrest induced by BCR-ABL antagonists and accelerates death of chronic myelogenous leukemia cells.Cell death discovery · 2025Article
- Targeted Degradation of SOS1 Exhibits Potent Anticancer Activity and Overcomes Resistance in KRAS-Mutant Tumors and BCR-ABL-Positive Leukemia.Cancer research · 2025Article
- Acquired resistance to molecularly targeted therapies for cancer.Cancer drug resistance (Alhambra, Calif.) · 2025Review
- Mebendazole effectively overcomes imatinib resistance by dual-targeting BCR/ABL oncoprotein and β-tubulin in chronic myeloid leukemia cells.The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology · 2025Article
- Overcoming clinical BCR-ABL1 compound mutant resistance with combined ponatinib and asciminib therapy.Cancer cell · 2024Article
- Non-coding RNAs in leukemia drug resistance: new perspectives on molecular mechanisms and signaling pathways.Annals of hematology · 2024Review
- Insights into existing and futuristic treatment approach for chronic myeloid leukaemia.The Indian journal of medical research · 2024Review
- Loss of the vitamin D receptor triggers senescence in chronic myeloid leukemia via DDIT4-mediated DNA damage.Journal of molecular cell biology · 2024Article
- The therapeutic and biomarker significance of ferroptosis in chronic myeloid leukemia.Frontiers in immunology · 2024Article
- mTOR inhibition by AZD2014 alleviates BCR::ABL1 independent imatinib resistance through enhancing autophagy in CML resistant cells.American journal of cancer research · 2024Article
- Vaccine-boosted CAR T crosstalk with host immunity to reject tumors with antigen heterogeneity.Cell · 2023Article
- Protein Kinase C (PKC) Isozymes as Diagnostic and Prognostic Biomarkers and Therapeutic Targets for Cancer.Cancers · 2022Review
- Mechanisms of Resistance and Implications for Treatment Strategies in Chronic Myeloid Leukaemia.Cancers · 2022Review
20 more citing papers are in PubMed but not listed here.
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Authors and funding
14 authors at 3 institutions in 1 country.
Funding
Abstract
Resistance to the BCR-ABL inhibitor imatinib mesylate (IM) poses a major problem for the treatment of chronic myeloid leukemia (CML). IM resistance often results from a secondary mutation in BCR-ABL that interferes with drug binding. However, in many instances, there is no mutation in BCR-ABL, and the basis of such BCR-ABL-independent IM resistance remains to be elucidated. To gain insight into BCR-ABL-independent IM resistance mechanisms, we performed a large-scale RNA interference screen and identified IM-sensitizing genes (IMSGs) whose knockdown renders BCR-ABL(+) cells IM-resistant. In these IMSG knockdown cells, RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling is sustained after IM treatment because of up-regulation of PRKCH, which encodes the protein kinase C (PKC) family member PKCη, an activator of CRAF. PRKCH is also up-regulated in samples from CML patients with BCR-ABL-independent IM resistance. Combined treatment with IM and trametinib, a U.S. Food and Drug Administration-approved MEK inhibitor, synergistically kills BCR-ABL(+) IMSG knockdown cells and prolongs survival in mouse models of BCR-ABL-independent IM-resistant CML. Finally, we showed that CML stem cells contain high levels of PRKCH, and this contributes to their intrinsic IM resistance. Combined treatment with IM and trametinib synergistically kills CML stem cells with negligible effect on normal hematopoietic stem cells. Collectively, our results identify a therapeutically targetable mechanism of BCR-ABL-independent IM resistance in CML and CML stem cells.
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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.