Scientists at the Karolinska Institute in Sweden say they have created a new tool that identifies more reliably, and precisely which proteins are affected by particular drugs. The researchers developed their method by experimenting on lung cancer cells treated with 56 different kinds of drugs. For each of the drugs they first worked out the dose that kills half of the cells after 48 hours (LC50) and then used this dose for all the drugs.
Once half of the cells had died, they examined each cell’s proteome to ascertain which proteins the drugs targeted. In further experiments, they tested the drugs on other cells from breast and intestinal tumors and drew conclusions about the extent to which the drugs are specific or general in their targeting of cancer cells.
The results of these experiments are described in the searchable database that the researchers have now created, while the method itself (“ProTargetMiner as a proteome signature library of anticancer molecules for functional discovery”) is detailed in Nature Communications. The idea is for other researchers to be able to perform similar experiments with other drugs using the same model, and to thus expand the database with more target proteins for more substances.
“Deconvolution of targets and action mechanisms of anticancer compounds is fundamental in drug development. Here, we report on ProTargetMiner as a publicly available expandable proteome signature library of anticancer molecules in cancer cell lines. Based on 287 A549 adenocarcinoma proteomes affected by 56 compounds, the main dataset contains 7,328 proteins and 1,307,859 refined protein-drug pairs. These proteomic signatures cluster by compound targets and action mechanisms.
“The targets and mechanistic proteins are deconvoluted by partial least square modeling, provided through the website protargetminer.genexplain.com. For nine molecules representing the most diverse mechanisms and the common cancer cell lines MCF-7, RKO, and A549, deep proteome datasets are obtained. Combining data from the three cell lines highlights common drug targets and cell-specific differences. The database can be easily extended and merged with new compound signatures. ProTargetMiner serves as a chemical proteomics resource for the cancer research community and can become a valuable tool in drug discovery.”
“We find that the cells are killed in different ways by different drugs,” said Roman Zubarev, PhD, professor of medical proteomics at the Institute. “Not so long ago we used to think that cells could only die in three ways—necrosis, apoptosis, or autophagy—but now we’ve observed at least thirteen different ways in which cells can die. This method can help to speed up certain parts of the process of new drug development or improve our understanding of existing drugs.”