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Feedbacks and adaptive capabilities of the PI3K/Akt/mTOR axis in acute myeloid leukemia revealed by pathway selective
J Bertacchini1, M Guida2, B Accordi3
11] Department of Surgery, Medicine, Dentistry and Morphology, University of Modena and Reggio Emilia, Modena, Italy [2] Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
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.
Insights
Targeting Akt and mTOR in acute myeloid leukemia (AML) unexpectedly activated signaling pathways. Dual inhibition of Akt and receptor tyrosine kinases (RTKs) showed synergistic cytotoxic effects in AML cells.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Acute myeloid leukemia (AML) cells exhibit high phosphorylated Akt, a key regulator and drug target.
- The phosphatidylinositol 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is frequently hyperactivated in AML.
- Selective inhibitors targeting this axis are under investigation for AML treatment.
Purpose of the Study:
- To investigate the response of primary AML cells to inhibitors of the PI3K/Akt/mTOR pathway.
- To elucidate the mechanisms behind paradoxical signaling activation upon Akt and mTOR inhibition.
- To evaluate combination therapies targeting Akt and receptor tyrosine kinases (RTKs).
Main Methods:
- Reverse phase protein arrays (RPPA) were used to analyze 80 primary AML patient samples.
- Treatment with selective Akt (Akti 1/2) and mTOR (Torin1) inhibitors, alone and in combination.
- Analysis of downstream signaling effectors, including Forkhead box O (FoxO) and insulin receptor substrate-1 (IRS-1).
- Assessment of growth factor receptor tyrosine kinases (RTKs) expression and phosphorylation.
- Evaluation of cytotoxic effects of dual Akt and RTK inhibition.
Main Results:
- Over 60% of AML samples showed high pathway phosphorylation.
- Targeting Akt and mTOR paradoxically increased Akt phosphorylation and downstream signaling in 70% of samples.
- Inhibition of Akt/mTOR stabilized downstream effectors, leading to RTK upregulation and pathway reactivation.
- Dual inhibition of Akt and RTKs demonstrated significant synergistic cytotoxicity in AML cells.
- Combined therapy more effectively downregulated Akt signaling compared to single agents.
Conclusions:
- Targeting the PI3K/Akt/mTOR axis alone can lead to paradoxical activation in AML.
- Upregulation of RTKs plays a crucial role in overcoming single-agent therapy.
- Dual inhibition of Akt and RTKs presents a promising therapeutic strategy for AML.
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