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.
Highlights
Inactivating mutations in a copy of the NF1 gene cause neurofibromatosis type 1 (NF1), an autosomal dominant condition characterized by formation of benign tumors and an increased risk of developing Malignant Peripheral Nerve Sheath Tumors (MPNST) [1,2,3]
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
Upon calculation of the median and average across all fraction affected (FA) values observed in the analysis (Figure 1B), a significant difference in response was observed between two groups of cell lines - SNF02.2 and SNF94.3 compared to SNF10.1 and SNF96.2 (p < 0.00001, Mann–Whitney– Wilcoxon test)
Summary
Inactivating mutations in a copy of the NF1 gene cause neurofibromatosis type 1 (NF1), an autosomal dominant condition characterized by formation of benign tumors and an increased risk of developing Malignant Peripheral Nerve Sheath Tumors (MPNST) [1,2,3]. Inactivating mutations in NF1 lead to elevated levels of RAS-GTP and increased RAS signaling [10, 11] Both benign neurofibromas (Schwann cell tumors) and MPNSTs ( Schwann lineage) are thought to follow the twohit mechanism, where the initiating tumor cell has most commonly lost the other NF1 allele by somatic mutation, rendering the cell deficient in neurofibromin activity. Because such cells have increased RAS activity, most approaches to developing treatments for MPNSTs have been focused on inhibiting targets downstream of RAS such as pathways associated with mTOR or MEK/MAPK [12,13,14,15]. This has been in part due to the difficulty in directly targeting the three major isoforms of RAS (HRAS, KRAS and NRAS), clinical toxicity when inhibiting multiple downstream pathways of RAS, and the lack of a clear single node to block [12, 13, 18,19,20,21]
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