ProTargetMiner: A proteome library of anticancer molecules for functional discovery

ABSTRACT: As a further development of our Functional Identification of drug Targets by Expression Proteomics (FITExP) method, a reference dataset was built of the proteomic responses of A549 human adenocarcinoma cells to 56 clinical and experimental anticancer molecules. For each molecule, a concentration was used killing 50% of the cells after 48 h. With 4557 proteins quantified across all treatments and controls, 11 orthogonal dimensions were found in factor analysis of the ProTargetMiner dataset, indicating the action of at least that many distinct cell death modalities. For convenience, the number of dimensions was reduced to three and two, thus producing a “death globe” and “death map”, respectively. As expected, molecules with similar mechanisms of action produced proteome signatures clustering together on the death globe and map. Interrogation of the dataset with partial least square modeling contrasting a given molecule against all other treatments unveiled drug targets and mechanistic proteins, even when the specific protein regulation was as subtle as a 15% change. The mechanisms of action were revealed by mapping the group of target candidates on known protein networks. The dataset allows for unique interrogation approaches, such as defining a set of co-regulated proteins. The core (“untouchable”) proteome consisting of proteins with steady expression levels unaffected by the treatments was also defined; they are found to be involved in proteasome and mRNA surveillance pathway. Finally, a list of proteins most affected by the drugs was compiled; these proteins encompass many known drug targets. The ProTargetMiner represents a resource that may be useful to the community of drug developers or scientists interested in drug action mechanisms and cell death modalities. ProTargetMiner can be easily extended to other drugs.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Lung

DISEASE(S): Lung Cancer

SUBMITTER: Amir Ata Saei  

LAB HEAD: Roman Zubarev

PROVIDER: PXD009644 | Pride | 2019-11-01

REPOSITORIES: Pride