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      •   BUIR Home
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      • Bilkent Theses
      • Theses - Department of Molecular Biology and Genetics
      • Dept. of Molecular Biology and Genetics - Master's degree
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      Detection of phosphorylation signatures specific to cancer-related PI3-Kinase isoforms p110α and p110β

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      Embargo Lift Date: 2023-08-02
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      Author(s)
      Sulaiman, Mahnoor
      Advisor
      Çizmecioğlu, Onur
      Date
      2023-01
      Publisher
      Bilkent University
      Language
      English
      Type
      Thesis
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      Abstract
      The PI3K signaling pathway is required for many physiological activities, but it is commonly disrupted during cancer formation. The PI3K p110α and βisoforms, encoded by the PIK3CA and PIK3CB genes, are lipid kinases that phosphorylate PIP2 to PIP3 to activate the PI3K pathway. However, the distinct molecular targets of these isoforms have yet to be discovered, making targeted treatment problematic. According to cancer genomics research, the PIK3CA gene is commonly altered in cancers, but the PIK3CB gene is frequently amplified. The clinical usage of Pan-PI3K inhibitors has resulted in significant side effects, prompting the development of isoform-specific inhibitors. However, it has been shown that these drugs trigger alternate signaling systems downstream, leading in resistance to single-agent treatment. Our research intends to uncover distinctive protein-protein interactions of PI3K isoforms, as well as the consequent different phospho-proteomic signatures, which might be crucial determinants of specific cellular activities. This will be accomplished by using isogenic MEF cells that are only dependent on the p110α or p110β isoforms, isoform-specific pharmacological inhibitors BYL-719 and KIN 193, and a high-resolution mass spectrometry-based method to determine the phosphorylation levels of these protein samples. The predictive biomarkers discovered in this study can be utilized to identify patients who will benefit from PI3K-targeted drugs and to better understand the resistance mechanisms that may arise in response to pathway inhibition.
      Keywords
      PI3K signalling
      PIK3CA isoform
      PIK3CB isoform
      Phosphoproteomics
      BYL719
      KIN193
      Cancer
      Resistance
      Mass spectrometry
      IMAC
      Phosphorylation
      Permalink
      http://hdl.handle.net/11693/112021
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