Abstract 3828: Genomic and pathway analyses provide insights into the mechanisms underlying malignant peripheral nerve sheath tumors
Authors: Kahen Elliot , Brohl Andrew S. , Yu Diana X. , Clark Justine , Cubitt Christopher L. , Sullivan Daniel M. , Reed Damon R. 
Published: July 2016

Background: Dysfunction of the NF1 gene, which occurs in patients with neurofibromatosis type 1, is associated with an increased risk of developing Malignant Peripheral Neural Sheath Tumor (MPNST). The neurofibromin protein is a negative regulator of RAS function and 1 in 10 neurofibromatosis type 1 patients develop MPNST in their young adult years. Effective chemotherapy treatments for MPNST are not available and the prognosis for unresectable or metastatic tumors is poor. Genome-wide sequencing of human MPNSTs has identified several key genes in MPNST including NF1, CDKN2A, TP53, SUZ12, and EED. Interestingly, high-throughput drug screening of FDA-approved chemotherapy agents demonstrated differential drug sensitivities amongst a panel of MPNST cell lines. Further elucidation of the molecular mechanisms underlying therapeutic responses in MPNST will allow the development of treatments catered to tumor genetics and may improve understanding of other RAS-associated diseases.

Methods: We used a combination of genomics, high-throughput drug screening, and pathway analysis to better understand how the oncogenic pathways important for MPNST development may dictate treatment outcomes. We performed whole exome sequencing of tumors from 5 MPNST patients as well as 4 established MPNST cell lines (SNF02.2, SNF10.1, SNF94.3, SNF96.2). In the cell lines, we additionally performed RNA sequencing and high-density SNP arrays. With the cell line models, we used our high-throughput screening platform to assess the efficacy of 54 agents of interest alone or in combination at clinically relevant doses, guided by published pharmacokinetics. The cell lines were further subjected to pathway analysis when subject to specific blockades downstream of RAS at the protein level with the use of immunoblotting and antibody arrays.

Results: Our sequencing results indicate alterations in NF1, CDKN2A, TP53, SUZ12, and EED are present in the tumors and cell lines studied. Using cell line models, the predicted genetic alterations resulted in striking and consistent effects on expression at both the RNA and protein level. Within our panel of four cell lines, there was a broad spectrum of NF1 activity, ranging from complete loss to normal expression of full-length transcript. Interestingly, we found that NF1 exhibited a spectrum of loss from unexpressed, to partial expression, and normal expression of the full-length transcript. We found that drug sensitivity to targets downstream of RAS is correlated with the degree of NF1 expression. These findings suggest promising opportunities for developing combination clinical trials that take into account a patients’ genetics in order to improve treatment outcomes.

Citation Format: Elliot Kahen, Andrew S. Brohl, Diana X. Yu, Justine Clark, Christopher L. Cubitt, Daniel M. Sullivan, Damon R. Reed. Genomic and pathway analyses provide insights into the mechanisms underlying malignant peripheral nerve sheath tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3828.