Targeting P53-Associated Therapy Resistance in NF1-Related MPNSTs
Abstract
Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are aggressive, highly chemo resistant sarcomas that are a leading cause of death in patients with Neurofibromatosis Type 1 (NF). NF is caused by germline mutations in the NF1 gene, which is the key negative regulatory gene of the RAS pathway and is mutated or deleted in a wide range of cancers. Loss of NF1 leads to deregulated RAS signaling, including the RAFMEKERK pathway. Currently, there is no effective chemotherapy or targeted therapy that is effective in MPNST patients. Even though there have been recent successes with RAF and MEK inhibitors in BRAF-mutated melanoma, innate and acquired resistance to kinase inhibition is a significant clinical issue. Resistance to kinase inhibitors is often promoted by adaptive kinome reprogramming of vital oncogenic signaling networks. The mechanisms and genomic alterations that regulate kinome reprogramming inNF1-deficient cancers are poorly understood. We have demonstrated that P53 deficiency significantly exacerbates resistance to MEK inhibition in our preclinical MPNST models. These results demonstrate that NF1-related MPNSTs maintain multiple signaling dependencies beyond RAS, and that genomic determinants, such as P53 genomic alterations, profoundly influence therapy response. In this proposal, we will combine integrated phosphoproteomic/genomic analyses, NF1-MPNST PDX models and a novel targeted NF1sequencing methodology to 1) untangle the kinome signaling architecture of MPNSTs; 2) determine kinome and genomic events that drive MPNST progression and therapeutic resistance; and 3) identify effective combination therapies for MPNST patients. The results of these studies will significantly advance our understanding of NF1-mediated RAS deregulation and the proteogenomic adaptations that promote therapeutic resistance
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2022
- Accession Number
- AD1190609
Entities
People
- Matthew R. Steensma