Abstract PO-115: Defining mechanisms of resistance in NF1-related malignant peripheral nerve sheath tumors
Authors: McGee Lauren , Grit Jamie , Essenburg Curt , Graveel Carrie , Steensma Matt 
Published: December 2020

Malignant peripheral nerve sheath tumors (MPNSTs) are rare and deadly sarcomas with few therapeutic options. Particularly common in individuals with the tumor predisposition syndrome Neurofibromatosis Type 1 (NF1), MPNSTs are the leading cause of death for NF1 patients and are largely resistant to chemotherapy, with large burden of genomic alterations that make any early response to treatment quickly followed by the development of resistance. NF1 is the major negative regulator of RAS, therefore one of the hallmarks of MPNST is deregulated RAS signaling leading to activation of MEK/ERK. Currently, no targeted therapy has been approved for NF1-related MPNSTs, highlighting the need for a better understanding of the complex signaling in MPNSTs and how mechanisms of resistance arise. To investigate the molecular mechanisms behind NF1-related MPNST resistance, we are using both in vitro and in vivo assays including a drug matrix combination platform and an in vivo model of drug resistance. Using xenografts of NF1-related MPNST germline models, we use a drug holiday approach to promote resistance to targeted kinase inhibition, such as MET and MEK inhibitors. For example, treatment with the MEK inhibitor trametinib initially reduce tumor burden, however after a brief “drug holiday” where the mice received no treatment, tumors regrew and were treated with either a MET inhibitor or a combination of MET and MEK inhibitors. Analysis of these tumors indicate a number of altered pathways that may contribute to resistance, including an upregulation of AKT signaling. These results indicate the need for a closer look at the PI3K/AKT signaling and their role in the resistance in NF1-related MPNSTs. To target adaptive AKT activation upon MEK inhibition we utilized the upregulation of AKT with MEK inhibitor treatment in a matrix drug combination platform using human NF1-related MPNST cell lines. In human MPNST cells, we observed that AKT inhibitors alone or in combination with a MEK inhibitor are not effective in reducing human MPNST cell viability. This is likely due to the presence of complex genomic alterations in these lines and RTK crosstalk signaling that promotes kinome plasticity. Currently we are evaluating other pathways that have been found to drive MEK inhibitor resistance in other RAS-driven cancers. Additionally, we are applying the “drug holiday” approach to a panel of patient derived xenograft (PDX) MPNST models to identify the diversity of resistance mechanisms that are likely present in NF1-related MPNST patients. These studies will enhance our understanding of how genomic alterations in NF1-related MPNST patients promote resistance and identify potential novel therapeutic targets.

Citation Format: Lauren McGee, Jamie Grit, Curt Essenburg, Carrie Graveel, Matt Steensma. Defining mechanisms of resistance in NF1-related malignant peripheral nerve sheath tumors [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-115.