ArticleLeukemia2005
Compensatory PI3-kinase/Akt/mTor activation regulates imatinib resistance development.
Article in Leukemia, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 102 papers.
What it found
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Who cites it
102 citing papers in PubMed.
- Dasatinib rapidly induces deep molecular response in chronic-phase chronic myeloid leukemia patients who achieved major molecular response with detectable levels of BCR-ABL1 transcripts by imatinib therapy.International journal of clinical oncology · 2017Trial
- Understanding drug resistance in chronic myeloid leukemia through the lens of leukemic stem cell states: insights from single-cell analyses.Haematologica · 2026Review
- Article
- Therapeutic Targets for Overcoming BCR::ABL1 Tyrosine Kinase Inhibitor Resistance in Chronic Myeloid Leukemia.Oncology research · 2026Review
- Exploiting artificial intelligence in precision oncology: an updated comprehensive review.Journal of translational medicine · 2025Review
- Genes-first and phenotypes-first paths to treatment resistance in hematological malignancies.Cell death & disease · 2025Review
- Investigation of TSRP reverses imatinib resistance through the PI3K / Akt pathway in chronic myeloid leukemia.Annals of hematology · 2024Article
- Identification of exosomal microRNAs and related hub genes associated with imatinib resistance in chronic myeloid leukemia.Naunyn-Schmiedeberg's archives of pharmacology · 2024Article
- Review
- CX‑5461 potentiates imatinib‑induced apoptosis in K562 cells by stimulatingExperimental and therapeutic medicine · 2024Article
- mTOR inhibition by AZD2014 alleviates BCR::ABL1 independent imatinib resistance through enhancing autophagy in CML resistant cells.American journal of cancer research · 2024Article
- Kinase-independent role of mTOR and on-/off-target effects of an mTOR kinase inhibitor.Leukemia · 2023Article
- Discrimination of the chemotherapy resistance status of human leukemia and glioblastoma cell lines by MALDI-TOF-MS profiling.Scientific reports · 2023Article
- Mechanisms of Resistance and Implications for Treatment Strategies in Chronic Myeloid Leukaemia.Cancers · 2022Review
- The active kinome: The modern view of how active protein kinase networks fit in biological research.Current opinion in pharmacology · 2022Review
- BCR-ABL1 Tyrosine Kinase Complex Signaling Transduction: Challenges to Overcome Resistance in Chronic Myeloid Leukemia.Pharmaceutics · 2022Review
- Tanshinone IIA potentiates the efficacy of imatinib by regulating the AKT-MDM2-P53 signaling pathway in Philadelphia chromosome-positive acute lymphoblastic leukemia.Oncology letters · 2022Article
- Overcoming Resistance to Kinase Inhibitors: The Paradigm of Chronic Myeloid Leukemia.OncoTargets and therapy · 2022Review
- Consensus molecular subtype 4 (CMS4)-targeted therapy in primary colon cancer: A proof-of-concept study.Frontiers in oncology · 2022Article
- Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia-From Molecular Mechanisms to Clinical Relevance.Cancers · 2021Review
42 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
10 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
BCR/ABL-kinase mutations frequently mediate clinical resistance to the selective tyrosine kinase inhibitor Imatinib mesylate (IM, Gleevec). However, mechanisms that promote survival of BCR/ABL-positive cells before clinically overt IM resistance occurs have poorly been defined so far. Here, we demonstrate that IM-treatment activated the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTor)-pathway in BCR/ABL-positive LAMA-cells and primary leukemia cells in vitro, as well as in a chronic phase CML patient in vivo. In fact, PI3K/Akt-activation critically mediated survival during the early phase of IM resistance development before manifestation of BCR/ABL-dependent strong IM resistance such as through a kinase mutation. Accordingly, inhibition of IM-induced Akt activation using mTor inhibitors and Akt-specific siRNA effectively antagonized development of incipient IM-resistance in vitro. In contrast, IM-resistant chronic myeloid leukemia (CML) patients with BCR/ABL kinase mutations (n=15), and IM-refractory BCR/ABL-positive acute lymphatic leukemia patients (n=2) displayed inconsistent and kinase mutation-independent autonomous patterns of Akt-pathway activation, and mTor-inhibition overcame IM resistance only if Akt was strongly activated. Together, an IM-induced compensatory Akt/mTor activation may represent a novel mechanism for the persistence of BCR/ABL-positive cells in IM-treated patients. Treatment with mTor inhibitors may thus be particularly effective in IM-sensitive patients, whereas Akt-pathway activation variably contributes to clinically overt IM resistance.
Indexed as
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16136169What OpenQuestion holds
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.