This thesis seeks to investigate how cancer-associated mutations affect the pharmacological properties of selected GPCRs—primarily A2AAR and 5-HT2CR—through a combination of ligand binding assays, signaling readouts, kinetic profiling, and cellular functional assays. By characterizing the functional consequences of naturally occurring missense mutations, this work aims to shed light on the broader question of whether such mutations could serve as biomarkers for treatment stratification or as targets for novel therapeutic strategies.
In Chapter 2, a comprehensive review outlines the current understanding of GPCR-G protein signaling in the context of cancer and summarizes the mutational landscape of GPCRs identified from large-scale cancer datasets. The chapter also discusses whether GPCR mutations identified in cancer act as drivers or passengers, and the methodological and conceptual challenges in making this distinction.
Show moreThis thesis seeks to investigate how cancer-associated mutations affect the pharmacological properties of selected GPCRs—primarily A2AAR and 5-HT2CR—through a combination of ligand binding assays, signaling readouts, kinetic profiling, and cellular functional assays. By characterizing the functional consequences of naturally occurring missense mutations, this work aims to shed light on the broader question of whether such mutations could serve as biomarkers for treatment stratification or as targets for novel therapeutic strategies.
In Chapter 2, a comprehensive review outlines the current understanding of GPCR-G protein signaling in the context of cancer and summarizes the mutational landscape of GPCRs identified from large-scale cancer datasets. The chapter also discusses whether GPCR mutations identified in cancer act as drivers or passengers, and the methodological and conceptual challenges in making this distinction.
Chapters 3 and 4 focus on the adenosine A2A receptor, analyzing how specific cancer-associated mutations influence ligand-receptor interactions and receptor function. Using both classical and newly developed agonists and antagonists, these chapters delve into how pharmacological parameters such as binding affinity and residence time, potency and efficacy are affected by structural alterations in the receptor. The implications of these findings for cancer cell behavior and therapeutic strategies are also discussed.
In Chapter 5, the functional role of A2AAR and A2BAR in cancer cell growth is investigated using breast cancer cell lines. The study evaluates the impact of pharmacological activation and inhibition, and discusses how receptor signaling contributes to cancer progression in a cell type dependent manner. This chapter provides an important link between in vitro pharmacology and oncogenic phenotypes.
Chapter 6 shifts focus to the 5-HT2C receptor, another GPCR with oncogenic potential. Using a similar approach as with A2AAR, this chapter investigates how cancer-associated 5-HT2CR mutations affect receptor pharmacology, including ligand binding and signal transduction. Despite the dispersed nature of these mutations, the study identifies several variants with altered functional profiles, suggesting potential relevance to cancer biology.
Chapter 7 summarizes the findings presented in this thesis, offering a thorough discussion of how mutations can rewire GPCR pharmacology in a context-dependent manner. These insights underscore the need for case-by-case characterization of GPCR variants, especially in cancer where receptor function and therapeutic response are tightly linked to the cellular environment. This chapter also highlights underexplored opportunities, such as covalent ligands, biased signaling, and allosteric modulation as promising strategies to overcome drug resistance associated with GPCR mutations. Taken together, by combining molecular pharmacology, cancer biology, and translational perspectives, this thesis contributes to a growing recognition of GPCRs as dynamic and druggable nodes in cancer signaling networks.
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