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.
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Acknowledgements
We thank Novartis Pharma GmbH, Nürnberg, Germany for providing everolimus and imatinib. We appreciate the assistance of Drs Wollmer and Wündisch in collecting clinical samples and Mrs Rehn and Mrs Barrett for their excellent technical assistance. This work was supported by the Deutsche José Carreras Leukämie-Stiftung e.V. (to AB), by the PE Kempkes Stiftung (to AB), by the Deutsche Forschungsgemeinschaft, Transregio 17 (to AB and AN), by grants from the German Ministry of Education and Research (BMBF), Kompetenznetz: Akute und chronische Leukämien – 01 GI9980/6, 01G19971 and the German Genome Research Network (NGFN).
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Burchert, A., Wang, Y., Cai, D. et al. Compensatory PI3-kinase/Akt/mTor activation regulates imatinib resistance development. Leukemia 19, 1774–1782 (2005). https://doi.org/10.1038/sj.leu.2403898
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DOI: https://doi.org/10.1038/sj.leu.2403898
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