The cellular thermal shift assay (CETSA) for elucidating drug mechanism of action and resistance in cancer

Sammanfattning: A complete understanding over drug mechanism of action (MoA) is important when attempting to predict treatment outcome or the presence of resistance in patients. Despite decades of scientific efforts, the MoAs of even some of the oldest and most utilized drugs in cancer therapy today remain only partially understood, while resistance continues to be a frequent and often unpredictable occurrence. The absence of a protein-focused systems-wide characterization of drug-induced changes in cellular states contributes to these gaps in knowledge, as proteins are difficult to study yet they are key players in nearly all cellular processes and the targets for most drugs. The cellular thermal shift assay (CETSA) is a recently introduced method that can directly monitor drug target engagement and drug-induced cellular changes at proteome level in intact living cells. The research presented in this thesis focuses on the protein-centric CETSA approach to charting drug MoA and resistance development by evaluating the drug-induced changes in protein thermal stability for several important cancer drugs utilized in the clinic e.g. pyrimidine analogues, taxanes, or apoptosisblockade releasing compounds in intact living cells or tissues. We report on an extensive set of CETSA responses that reflect on drug-target engagement or other MoA-revealing alterations in cellular processes that are either compound-specific or overlapping between some of the studied drugs. Several of the highlighted proteins or ensembles of proteins show promise for further evaluation as candidate biomarkers for drug efficacy with potential future applications in a clinical setting.

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