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Related Concept Videos

Genetic Screens02:46

Genetic Screens

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Genetic screens are tools used to identify genes and mutations responsible for phenotypes of interest. Genetic screens help identify individuals or a group of people at risk of developing  genetic diseases and help them with early intervention, targeted therapy, and reproductive options.
Forward genetic screens
Forward or “classical” genetic screens involve creating random mutations in an organism’s DNA using radiation, mutagens, or insertion of additional bases, which...
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The Ras Gene02:38

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Small GTPases - Ras and Rho01:24

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Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
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The Ras Gene02:38

The Ras Gene

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The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
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A Multiplexed Luciferase-based Screening Platform for Interrogating Cancer-associated Signal Transduction in Cultured Cells
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Development of a High-Throughput Gene Expression Screen for Modulators of RAS-MAPK Signaling in a Mutant RAS Cellular

Bryan Severyn1, Thi Nguyen2, Michael D Altman3

  • 1Screening and Protein Sciences, Merck & Co. Inc., North Wales, PA, USA Bryan_severyn@merck.com.

Journal of Biomolecular Screening
|July 28, 2016
PubMed
Summary
This summary is machine-generated.

Researchers developed a gene expression assay to screen for drugs targeting the RAS-MAPK pathway in colorectal cancer. This assay successfully identified compounds that inhibit key pathway members, offering a new tool for cancer therapy development.

Keywords:
MAPK pathwaychemical genomicscolon cancergene expression high-throughput screenxMAP technology

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Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • The RAS-MAPK pathway is crucial for cellular functions and is frequently dysregulated in colorectal cancers, driving neoplasm development.
  • Mutations in this pathway lead to aberrant signaling, making it a promising target for therapeutic interventions.

Purpose of the Study:

  • To develop and validate a gene expression-based high-throughput screening (GE-HTS) assay for identifying modulators of the RAS-MAPK pathway.
  • To discover novel compounds targeting the RAS-MAPK pathway for potential colorectal cancer therapies.

Main Methods:

  • Developed a 26-gene signature for RAS-MAPK pathway activity using the Affymetrix QuantiGene Plex 2.0 system.
  • Performed primary and confirmatory GE-HTSs using KRAS mutant colon cancer cells and a chemical library.
  • Validated hits through dose-response assays, additional cell line testing, and in vitro colony formation assays.

Main Results:

  • The GE-HTS assay achieved a 1.4% hit rate and successfully enriched for compounds targeting MEK and EGFR.
  • Demonstrated high sensitivity (0.84) and selectivity (1.00) for the assay.
  • Confirmed active compounds across multiple assays and cell lines.

Conclusions:

  • The developed GE-HTS assay is a robust tool for identifying novel compounds and mechanisms that modulate the RAS-MAPK pathway.
  • This assay can facilitate larger, unbiased chemical screens for developing new colorectal cancer therapeutics.