Costa, Maria Claudia (2024) Uncovering the activity of master kinases in cancers by system biology approaches. [Tesi di dottorato]

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Abstract

Understanding the lack of anti-tumor immune response that characterizes numerous cancer patients is a major focus of current research, highlighting the need to clarify the basis of “Immune-cold" tumors in order to improve therapeutic strategies. This study leverages multi-omics data from ten cancer types from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) to identify Master Kinases as regulators of immune-deficient phenotypes at a pan-cancer level. Our approach involves (i) immune profiling via Immunologic Constant of Rejection (ICR) expression analysis, (ii) construction of protein kinase-substrate interaction networks through a system-biology approach, and (iii) computation of a kinase-specific Activity score for each patient. In this framework, we confirmed for the first time the robustness of the ICRbased classification on the CPTAC database, defining Immune-hot and Immune-cold tumors pan-cancer. Moreover, we demonstrated that the Activity score effectively captures valuable biological and functional information when compared to proteomics abundance data, describing 19 master kinases predicted to regulate the Immune-cold profiles across cancers, thereby identifying potential therapeutic targets. Notably, we observed that a high CDK5 activity is associated with a poor prognosis across the cohorts and could be linked to enhanced DNA repair and tumor spread by indirectly regulating acetylation patterns. Additionally, we returned that CDK5, GSK3α, and GSK3β increase their activity in patients harboring STK11/LKB1 mutations, especially in Lung Adenocarcinoma (LUAD). In particular, these kinases are likely critical effectors of pathway rewiring in STK11/LKB1-mutated patients, for which an immunosuppressed microenvironment has been previously established. These findings provide valuable insight into the main mechanisms driving Immune-cold tumors, uncovering potentially targetable kinases that could drive novel therapeutic strategies, with the ultimate purpose of re-establishing the immune response and improving patient outcomes.

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