Proteomics

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A mass spectrometry-based proteome map of drug action in lung cancer cell lines Part 6

ABSTRACT: Mass spectrometry-based discovery proteomics is an essential tool for the proximal read-out of cellular drug action. Here, we used a robust proteomic workflow to rapidly and systematically profile the proteomes of five cell lines in response to > 50 drugs. We found that aggregating millions of quantitative protein-drug associations substantially improved the mechanism of action (MoA) deconvolution of single compounds. For example, MoA specificity increased after removal of proteins which frequently responded to drugs and the aggregation of proteome changes across multiple cell lines resolved compound effects on proteostasis. These characteristics were further leveraged to demonstrate efficient target identification of protein degraders. Moreover, we followed up on selected proteomic findings and showed that the inhibition of mitochondrial function is an off-target mechanism of the clinical MEK inhibitor PD184352 and that Ceritinib, an FDA approved drug in lung cancer, modulates autophagy. Overall, this study demonstrates that large-scale proteome perturbation profiling can be a useful addition to the drug discovery toolbox.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: An Chi  

PROVIDER: MSV000087955 | MassIVE | Fri Aug 06 21:55:00 BST 2021

SECONDARY ACCESSION(S): PXD018574

REPOSITORIES: MassIVE

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Publications

The role of windows of selection and windows of dominance in the evolution of insecticide resistance in human disease vectors.

South Andy A   Lees Rosemary R   Garrod Gala G   Carson Jessica J   Malone David D   Hastings Ian I  

Evolutionary applications 20191210 4

Persistent insecticides sprayed onto house walls, and incorporated into insecticide-treated bednets, provide long-acting, cost-effective control of vector-borne diseases such as malaria and leishmaniasis. The high concentrations that occur immediately postdeployment may kill both resistant and susceptible insects. However, insecticide concentration, and therefore killing ability, declines in the months after deployment. As concentrations decline, resistant insects start to survive, while suscept  ...[more]

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