Characterization of NTRK2 and NTRK3 Mutations in Cancer

Abstract

Neurotrophin tyrosine receptor kinases (NTRK) play a seminal role in central nervous system development, and are expressed in various peripheral tissues in the body. NTRKs regulate cellular function through the activation of canonical cell growth and survival pathways such as MAPK and PI3K. Genetic aberrations that activate NTRK function have recently been shown to be promising drug targets in lung cancer, sarcoma, and neuroblastoma, but their role in hematologic malignancies has not yet been reported. In this two-part thesis, I combine experimental data from my laboratory work at the Oregon Health and Science University with a bioinformatics project at Princeton to understand the role of somatic point mutations in NTRK. At OHSU, I characterized four novel activating point mutations in NTRK that were identified from primary leukemia sample, which demonstrated sensitivity to the NTRK inhibitor, entrectinib, in model systems. In the computational portion of my project, I analyzed NTRK mutations across a wider range of cancer types, pulling clinical and mutational information from online databases such as The Cancer Genome Atlas, cBioPortal, and the St. Jude Pediatric Cancer Database, in order to identify additional mutations that may act as oncogenic drivers of cancer. My results suggest that NTRK mutations may play a role in leukemogenesis by activating downstream pathways and could serve as potential therapeutic targets in patients harboring NTRK mutations. In addition, I have systemically identified potentially activating mutations in NTRK by analyzing mutation burden by protein domain and by cancer type. Future experiments should work to fully assess the molecular characteristics of these mutations and to demonstrate the effects of entrectinib targeting NTRKs through in vitro and in vivo validation.