Abstract

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.

Highlights

  • Neurofibromatosis Type 1 (NF1) is an autosomal dominant disease that is caused by loss of function-mutations and/or deletions in the tumour suppressor gene neurofibromin 1 (NF1)

  • Persistent signalling via the PI3K/AKT/mTOR pathway is a major driver of malignancy in NF1-associated malignant peripheral nerve sheath tumours (MPNST)

  • 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

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Summary

Introduction

Neurofibromatosis Type 1 (NF1) is an autosomal dominant disease that is caused by loss of function-mutations and/or deletions in the tumour suppressor gene neurofibromin 1 (NF1). The malignant transformation of PNF is not the most common complication (8–13% lifetime risk) in Neurofibromatosis Type 1 patients, MPNST are associated with the highest mortality among complications, with a 5-year survival rate of less than 30% [8,10,11]. Pharmacological inhibition of the RAS/RAF/MEK/MAPK cascade has been demonstrated to slow down tumour growth and increase overall survival of mice bearing MPNST xenografts [15]. Targeting the mTOR pathway by rapamycin has been demonstrated to have an effect on NF1-associated tumours in an engineered mouse model of NF1 [3]. We demonstrate that dual targeting of AKT with the allosteric pan-AKT inhibitor MK-2206 and mTOR using the mTORC1/mTORC2 bi-specific ATP-competitor AZD8055 is sufficient to significantly decrease NF1-null MPNST cell viability in vitro. We show that additional inhibition with the MEK inhibitor AZD6244 shows synergistic effects on the viability of MPNST cells in vitro

Results
C S462sp
Dual Targeting of AKT and mTOR does not Inhibit MPNST Growth in Vivo
Cell Culture
Proliferation Assay
In Vivo Xenograft Model
Western Blot
Statistical Analysis
Determination of Synergistic Effects
Full Text
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