Dissertation/Thesis Abstract

Investigating RAS and RTK Signaling in MPNST Progression
by King, Candace Nicole, M.S., Van Andel Research Institute, 2019, 65; 27539460
Abstract (Summary)

Neurofibromatosis, type 1 (NF1) is a tumor predisposition syndrome affecting about 1 in 2500 live births in the United States. In this disease, the protein product of the NF1 gene, neurofibromin, loses its function as a negative regulator of the RAS protein, leading to the development of painful and disfiguring benign tumors known as neurofibromas. Plexiform neurofibromas in 8% to 13% of patients will transform into malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are aggressive soft tissue sarcomas that respond poorly to chemotherapy and surgical resection. The poor clinical outcome of NF1 patients presents a critical need for efficacious targeted therapy to improve survival rates. Current targeted therapy efforts have shown modest efficacy due to the establishment of compensatory feedback mechanisms that promote tumor progression and recurrence. These feedback mechanisms are poorly understood in MPNSTs. In lung cancer, inhibition of MEK in the RAS pathway activates upstream receptor tyrosine kinases (RTK). Phosphorylated MEK is overexpressed in > 90% of MPNSTs compared to 21% of benign neurofibromas. Genomic studies of MPNST samples have shown that 30% of tumors have amplification of the RTKs MET and EGFR. Our laboratory examined the genomic progression of a NF1 MPNST patient pre- and post-treatment and observed increased MET and EGFR amplification following treatment. In triple negative breast cancer cells, MET and EGFR crosstalk may be responsible for the reactivation of the inhibited cancer pathways and drug resistance. Therefore, the hypothesis for this project is that coordinated deregulated RAS signaling and MEK inhibition leads to MET and EGFR amplification, expression, activation, and crosstalk which drives MPNST progression, drug resistance, and tumor recurrence. To test my hypothesis, I pursued the following specific aims: (1) determined a proteogenomic signature that provides insight into the signaling and genomic changes that are involved in NF1-related MPNST progression, (2) predicted the emergence of feedback loops that explain TKI resistance in MPNSTs as well as predict tumor response to MPNST monotherapy inhibition, (3) identified effective treatment strategies based on established proteogenomic signatures. I determined the impact of MEK inhibition on RTK expression and deregulated RAS downstream signaling before and after treatment with MEK and RTK inhibitors in diverse human MPNST cell lines with distinct MET and EGFR expression and activation profiles. I also determined the impact of MEK-RTK inhibition on tumor cell viability, apoptosis, and invasion.

The long-term goal of this project was to identify predictive markers of targeted drug resistance in MPNST patients that could serve as targets for therapy. This project increases the knowledge of targeted therapeutic options for MPNST patients, which could decrease mortality rates associated with MPNSTs.

Indexing (document details)
Advisor: Steensma, Matthew
Commitee: Graveel, Carrie, Grohar, Patrick, Williams, Bart, Dodd, Rebecca
School: Van Andel Research Institute
Department: Biomedical
School Location: United States -- Michigan
Source: MAI 81/4(E), Masters Abstracts International
Source Type: DISSERTATION
Subjects: Oncology, Cellular biology, Molecular biology
Keywords:
Publication Number: 27539460
ISBN: 9781687965721
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