Neurofibromin level directs RAS pathway signaling and mediates sensitivity to targeted agents in malignant peripheral nerve sheath tumors.

Abstract

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.

• Authors: Elliot John Kahen, Andrew Brohl, Diana Yu, Darcy Welch, Christopher L Cubitt, Jae K Lee, Yunyun Chen, Sean J Yoder, Jamie K Teer, Yonghong O Zhang, Margaret R Wallace, Damon R Reed
• Journal: Oncotarget (Oncotarget) Vol. 9 Issue 32 Pg. 22571-22585 (Apr 27 2018) ISSN: 1949-2553 [Electronic] United States
• PMID: 29854299 (Publication Type: Journal Article)