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Feedbacks and adaptive capabilities of the PI3K/Akt/mTOR axis in acute myeloid leukemia revealed by pathway selective inhibition and phosphoproteome analysis

Leukemia volume 28, pages 2197–2205 (2014)Cite this article

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Abstract

Acute myeloid leukemia (AML) primary cells express high levels of phosphorylated Akt, a master regulator of cellular functions regarded as a promising drug target. By means of reverse phase protein arrays, we examined the response of 80 samples of primary cells from AML patients to selective inhibitors of the phosphatidylinositol 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) axis. We confirm that >60% of the samples analyzed are characterized by high pathway phosphorylation. Unexpectedly, however, we show here that targeting Akt and mTOR with the specific inhibitors Akti 1/2 and Torin1, alone or in combination, result in paradoxical Akt phosphorylation and activation of downstream signaling in 70% of the samples. Indeed, we demonstrate that cropping Akt or mTOR activity can stabilize the Akt/mTOR downstream effectors Forkhead box O and insulin receptor substrate-1, which in turn potentiate signaling through upregulation of the expression/phosphorylation of selected growth factor receptor tyrosine kinases (RTKs). Activation of RTKs in turn reactivates PI3K and downstream signaling, thus overruling the action of the drugs. We finally demonstrate that dual inhibition of Akt and RTKs displays strong synergistic cytotoxic effects in AML cells and downmodulates Akt signaling to a much greater extent than either drug alone, and should therefore be explored in AML clinical setting.

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Acknowledgements

SM and JB acknowledge the ‘International short term mobility program’ from Italian CNR and Fondazione CaRiMo, respectively; MG was in part supported by Fondazione Angela Serra for Cancer Research, Modena, Italy. This work was supported by grants from Italian MIUR-Prin 2008, Istituto Superiore Sanita’ oncoproteome network, prot. 2011-527TR1, and MIUR/FIRB accordi di programma 2010.

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  1. M Guida and B Accordi: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Surgery, Medicine, Dentistry and Morphology, University of Modena and Reggio Emilia, Modena, Italy

    J Bertacchini, M Guida, L Mediani, A De Pol & S Marmiroli

  2. Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy

    J Bertacchini, A M Martelli & L Cocco

  3. Department of Woman’s and Child’s Health, University of Padova, Padova, Italy

    B Accordi, G Milani, M Giordan & G Basso

  4. Department of Medical and Surgical Science, Section of Hematology, University of Modena and Reggio Emilia, Modena, Italy

    P Barozzi, M Luppi & F Forghieri

  5. Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA

    E Petricoin III & L Liotta

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  1. J Bertacchini
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Bertacchini, J., Guida, M., Accordi, B. et al. Feedbacks and adaptive capabilities of the PI3K/Akt/mTOR axis in acute myeloid leukemia revealed by pathway selective inhibition and phosphoproteome analysis. Leukemia 28, 2197–2205 (2014). https://doi.org/10.1038/leu.2014.123

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