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Updated: Jul 7, 2026
12:40
A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
Compensatory PI3-kinase/Akt/mTor activation regulates imatinib resistance development
1Klinikum der Philipps Universität Marburg, Klinik für Hämatologie, Onkologie und Immunologie, Marburg, Germany. burchert@mailer.uni-marburg.de
Leukemia
|September 2, 2005
Summary
Imatinib treatment activates the survival pathway phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTor) in leukemia cells, contributing to early resistance. Inhibiting this pathway may improve treatment efficacy in imatinib-sensitive patients.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- BCR/ABL-kinase mutations often cause resistance to Imatinib mesylate (IM) in leukemia treatment.
- Mechanisms promoting survival of BCR/ABL-positive cells during early IM resistance are not well understood.
Purpose of the Study:
- To investigate the role of the PI3K/Akt/mTor pathway in early IM resistance.
- To evaluate the potential of targeting this pathway to overcome IM resistance.
Main Methods:
- Treatment of BCR/ABL-positive cell lines and primary leukemia cells with IM.
- Analysis of PI3K/Akt/mTor pathway activation.
- Inhibition of Akt using mTor inhibitors and Akt-specific siRNA.
- Assessment of IM resistance in patients with BCR/ABL kinase mutations.
Main Results:
- IM treatment activated the PI3K/Akt/mTor pathway in BCR/ABL-positive cells, mediating survival during early IM resistance development.
- Inhibition of IM-induced Akt activation antagonized incipient IM resistance in vitro.
- In IM-resistant patients, Akt-pathway activation was inconsistent and mutation-independent.
- mTor inhibition overcame IM resistance only when Akt was strongly activated.
Conclusions:
- IM-induced compensatory Akt/mTor activation is a novel mechanism for BCR/ABL-positive cell persistence.
- Targeting the Akt/mTor pathway may be particularly effective in IM-sensitive patients.
- Akt-pathway activation contributes variably to clinically overt IM resistance.
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