Detection of phosphorylation signatures specific to cancer-related PI3-Kinase isoforms p110α and p110β

Date
2023-01
Advisor
Çizmecioğlu, Onur
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Bilkent University
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English
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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.

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PI3K signalling, PIK3CA isoform, PIK3CB isoform, Phosphoproteomics, BYL719, KIN193, Cancer, Resistance, Mass spectrometry, IMAC, Phosphorylation
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Published Version (Please cite this version)