Neurofibromin level directs RAS pathway signaling and mediates sensitivity to targeted agents in malignant peripheral nerve sheath tumors
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Elliot John Kahen1, Andrew Brohl2, Diana Yu1, Darcy Welch1, Christopher L. Cubitt1, Jae K. Lee3, Yunyun Chen3, Sean J. Yoder4, Jamie K. Teer3, Yonghong O. Zhang3, Margaret R. Wallace5 and Damon R. Reed1,2,6,7
1Sunshine Project Translational Research Lab, Tampa, FL 33612, Florida, USA
2Sarcoma Department, Tampa, FL 33612, Florida, USA
3Department of Biostatistics and Bioinformatics Tampa, FL 33612, Florida, USA
4Molecular Genomics Core Facility, Tampa, FL 33612, Florida, USA
5Department of Molecular Genetics and Microbiology and UF Health Cancer Center, University of Florida, Tampa, FL 33612, Florida, USA
6Chemical Biology and Molecular Medicine Program, Tampa, FL 33612, Florida, USA
7Adolescent and Young Adult Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, Florida, USA
Damon R. Reed, email: [email protected]
Keywords: NF1; MPNST; RAS; combination therapy; MEK
Received: March 29, 2018 Accepted: April 04, 2018 Published: April 27, 2018
Malignant peripheral nerve sheath tumor (MPNST) is a type of soft-tissue sarcoma strongly associated with dysfunction in neurofibromin; an inhibitor of the RAS pathway. We performed high-throughput screening of an array of FDA approved and promising agents in clinical development both alone and in combination at physiologically achievable concentrations against a panel of established MPNST cell line models. We found that drugs targeting a variety of factors in the RAS pathway can effectively lead to cell death in vitro with considerable drug combination synergy in regimens that target MEK or mTOR. We observed that the degree of relative sensitivity to chemotherapeutic agents was associated with the status of neurofibromin in these cell line models. Using a combination of agents that target MEK and mTORC1/2, we effectively silenced RAS/PI3K/MEK/mTOR signaling in vitro. Moreover, we employed RNAi against NF1 to establish that MPNST drug sensitivity is directly proportional to relative level of intracellular neurofibromin. Thus, two-drug combinations that target MEK and mTORC1/2 are most effective in halting the RAS signaling cascade, and the relative success of this and related small molecule interventions in MPNSTs may be predicated upon the molecular status of neurofibromin.
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