A Drug Discovery Pipeline for MAPK/ERK Pathway Inhibitors in Caenorhabditis elegans.

Autor:	Gorgoń S; Department of Diagnostics and Intervention, Surgery, Umeå University, Umeå, Sweden., Billing O; Department of Diagnostics and Intervention, Surgery, Umeå University, Umeå, Sweden., Eriksson AU; Chemical Biology Consortium Sweden, Umeå University, Umeå, Sweden., Hemmingsson O; Department of Diagnostics and Intervention, Surgery, Umeå University, Umeå, Sweden.; Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden.
Jazyk:	angličtina
Zdroj:	Cancer research communications [Cancer Res Commun] 2024 Sep 01; Vol. 4 (9), pp. 2454-2462.
DOI:	10.1158/2767-9764.CRC-24-0221
Abstrakt:	Oncogenic signaling through the MAPK/ERK pathway drives tumor progression in many cancers. Although targeted MAPK/ERK pathway inhibitors improve survival in selected patients, most tumors are resistant. New drugs could be identified in small-animal models that, unlike in vitro models, can address oral uptake, compound bioavailability, and toxicity. This requires pharmacologic conformity between human and model MAPK/ERK pathways and available phenotypic assays. In this study, we test if the conserved MAPK/ERK pathway in Caenorhabditis elegans could serve as a model for pharmacological inhibition and develop in vivo pipelines for high-throughput compound screens. Using fluorescence-based image analysis of vulva development as a readout for MAPK/ERK activity, we obtained excellent assay Z-scores for the MEK inhibitors trametinib (Z = 0.95), mirdametinib (Z = 0.93), and AZD8330 (Z = 0.87), as well as the ERK inhibitor temuterkib (Z = 0.86). The throughput was 800 wells per hour, with an average seed density of 25.5 animals per well. Readouts included drug efficacy, toxicity, and pathway specificity, which was tested against pathway activating upstream (lin-15)- and downstream (lin-1) mutants. To validate the model in a high-throughput setting, we screened a blinded library of 433 anticancer compounds and identified four MEK inhibitors among seven positive hits. Our results highlight a high degree of pharmacological conformity between C. elegans and human MAPK/ERK pathways, and the presented high-throughput pipeline may discover and characterize novel inhibitors in vivo. Significance: Many tumors depend on MAPK/ERK signaling to sustain growth, avoid cell death, and metastasize. We show that specific and clinically relevant MAPK/ERK signaling inhibitors can be discovered in vivo with a high-throughput screening pipeline in small animals. (©2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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