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Characterization of Oncogenic Fusion BCR-FGFR1

  • Author(s): Peiris, Malalage Nicole
  • Advisor(s): Donoghue, Daniel J
  • et al.
Abstract

Fibroblast Growth Factor Receptors (FGFRs) are part of the Receptor Tyrosine Kinase (RTK) family and are essential in the activation of various downstream signaling pathways, which are necessary for cell differentiation and proliferation. However, mutation and translocation of FGFRs leads to aberrant activation of signaling, which often results in cancer. With the emergence of personalized medicine, cancer genome sequencing is vital in order to determine the appropriate therapies for patients. This work focuses on the t(8;22)(p11;q11) chromosomal translocation, which results in the fusion protein Breakpoint Cluster Region (BCR)-FGFR1 (BCR-FGFR1). BCR-FGFR1 is poorly characterized, resulting in few therapies and clinical advancements for patients positive for this fusion protein. This work focuses on the biochemical and biological characterization of BCR-FGFR1 along with the analysis of therapeutic options. The BCR-FGFR1 fusion shows transformation ability in NIH3T3 cells, and shows heavy activation of MAPK, STAT, and phospho-FGFR1 receptor. Additional phosphorylation sites on BCR-FGFR1 were identified through titanium dioxide based phosphopeptide-enriched Liquid chromatography/ mass spectrometry (LC/MS) analysis. Additionally, BCR contributes a coiled-coil dimerization domain to BCR-FGFR1; the importance of the dimerization domain is shown, as when disrupted, BCR-FGFR1 is unable to retain transforming ability. Lastly, BCR-FGFR1 is shown to be a client of the chaperone protein Hsp90 and is sensitive to Ganetespib (STA-9090), a potent Hsp90 inhibitor suggesting that BCR-FGFR1 relies on the Hsp90 complex to evade proteasomal degradation.

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