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Combined Targeting of AKT and mTOR Inhibits Proliferation of Human NF1-Associated Malignant Peripheral Nerve Sheath Tumour Cells In Vitro but not in a Xenograft Mouse Model In Vivo

1
Laboratory for Tumor Genetics, Department of Neurology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
2
Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
3
Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
4
Department of Diagnostic and Interventional Radiology and Nuclear Medicine, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(4), 1548; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21041548
Received: 4 February 2020 / Revised: 19 February 2020 / Accepted: 19 February 2020 / Published: 24 February 2020
(This article belongs to the Section Molecular Oncology)
Persistent signalling via the PI3K/AKT/mTOR pathway is a major driver of malignancy in NF1-associated malignant peripheral nerve sheath tumours (MPNST). Nevertheless, single targeting of this pathway is not sufficient to inhibit MPNST growth. In this report, we demonstrate that combined treatment with the allosteric pan-AKT inhibitor MK-2206 and the mTORC1/mTORC2 inhibitor AZD8055 has synergistic effects on the viability of MPNST cell lines in comparison to the treatment with each compound alone. However, when treating animals bearing experimental MPNST with the combined AKT/mTOR regime, no influence on tumour growth was observed. Further analysis of the MPNST xenograft tumours resistant to AKT/mTOR treatment revealed a reactivation of both AKT and mTOR in several tumour samples. Additional targeting of the RAS/RAF/MEK/MAPK pathway with the allosteric MEK1/2 inhibitor AZD6244 showed synergistic effects on the viability of MPNST cell lines in vitro in comparison to the dual AKT/mTOR inhibition. In summary, these data indicate that combined treatment with AKT and mTOR inhibitors is effective on MPNST cells in vitro but tumour resistance can occur rapidly in vivo by restoration of AKT/mTOR signalling. Our data further suggest that a triple treatment with inhibitors against AKT, mTORC1/2 and MEK1/2 may be a promising treatment option that should be further analysed in an experimental MPNST mouse model in vivo. View Full-Text
Keywords: MPNST; targeted therapy; AKT; neurofibromatosis type 1; signaling; xenograft model MPNST; targeted therapy; AKT; neurofibromatosis type 1; signaling; xenograft model
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MDPI and ACS Style

Schulte, A.; Ewald, F.; Spyra, M.; Smit, D.J.; Jiang, W.; Salamon, J.; Jücker, M.; Mautner, V.-F. Combined Targeting of AKT and mTOR Inhibits Proliferation of Human NF1-Associated Malignant Peripheral Nerve Sheath Tumour Cells In Vitro but not in a Xenograft Mouse Model In Vivo. Int. J. Mol. Sci. 2020, 21, 1548. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21041548

AMA Style

Schulte A, Ewald F, Spyra M, Smit DJ, Jiang W, Salamon J, Jücker M, Mautner V-F. Combined Targeting of AKT and mTOR Inhibits Proliferation of Human NF1-Associated Malignant Peripheral Nerve Sheath Tumour Cells In Vitro but not in a Xenograft Mouse Model In Vivo. International Journal of Molecular Sciences. 2020; 21(4):1548. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21041548

Chicago/Turabian Style

Schulte, Alexander, Florian Ewald, Melanie Spyra, Daniel J. Smit, Wei Jiang, Johannes Salamon, Manfred Jücker, and Victor-Felix Mautner. 2020. "Combined Targeting of AKT and mTOR Inhibits Proliferation of Human NF1-Associated Malignant Peripheral Nerve Sheath Tumour Cells In Vitro but not in a Xenograft Mouse Model In Vivo" International Journal of Molecular Sciences 21, no. 4: 1548. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21041548

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