Summary

Mechanism of action of cancer drugs
Even though cancer is primarily thought to be a genomic disease, mutations in cancer genomes often manifest themselves in the form of malfunctioning proteins. Not surprisingly, most cancer drugs directly act on protein targets or need an array of proteins to be activated in cells. Despite many years of successful clinical use, the full range of protein targets of a given drug, their (many) cellular mechanisms of action or mechanisms of resistance formation are not well understood. This is particularly true for kinase inhibitors that have emerged as important cancer therapies over the past 15 years.
In order to shed light on how cancer drugs actually work, we employ proteome wide measurements of drug-protein affinity in order to establish the full range of proteins that a drug may bind to and potentially inhibit or enhance its function. This can lead to a better understanding of how a drug works and why certain undesired side effects may occur. Importantly, it also offers perspectives of how an existing drug may be repurposed for a different indication.
To study the molecular mechanism of action of cancer drugs, we measure the activation status of signaling pathways and epigenetic networks in cancer cells. To do so, we employ proteome wide measurements of the post-translational modifications of proteins, notably phosphorylation, acetylation and ubiquitinylation. Understanding changes in these modifications induced by tumorigenesis or drug treatment in a quantitative fashion enables us to better understand why some cancers respond to therapy while others do not. This information can therefore be used for molecular diagnosis or stratification of patients for therapy.