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Genetic Screens

Genetic Screens

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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Related Experiment Video

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An Unbiased Functional Genetics Screen Identifies Rare Activating ERBB4 Mutations.

Deepankar Chakroborty^1,2,3,4, Veera K Ojala^1,2,3,4, Anna M Knittle¹

¹Institute of Biomedicine, University of Turku, Turku, Finland.

Cancer Research Communications

|March 2, 2023

Summary

Researchers identified rare activating ERBB4 mutations in cancer using a functional screen. These mutations, including E715K and R687K, showed hyperactivity and promoted tumor growth, but remained sensitive to pan-ERBB inhibitors, suggesting a therapeutic target.

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Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts

Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts

Published on: July 25, 2020

Area of Science:

Oncology
Molecular Biology
Genetics

Background:

The ERBB4 gene, part of the ERBB oncogene family, is frequently mutated in various cancers.
The functional consequences of most somatic ERBB4 mutations are largely unknown due to a lack of identified mutational hotspots.

Purpose of the Study:

To identify and functionally characterize activating mutations in the ERBB4 gene using an unbiased screening approach.
To assess the potential of these identified mutations as therapeutic targets for cancer treatment.

Main Methods:

An in vitro functional genetics screen was employed to analyze over 8,000 randomly mutated ERBB4 variants.
Selected mutations underwent functional validation in cell models and in vivo mouse allografts.
The sensitivity of identified ERBB4 mutants to pan-ERBB tyrosine kinase inhibitors was evaluated.

Main Results:

Two specific ERBB4 mutations, E715K and R687K, demonstrated hyperactivity across tested cell models.
These activating mutations promoted cellular proliferation in 2D and 3D cultures, with ERBB4 E715K also enhancing tumor growth in vivo.
All tested ERBB4 mutants exhibited sensitivity to clinically approved pan-ERBB inhibitors like afatinib, neratinib, and dacomitinib.

Conclusions:

Rare activating ERBB4 mutations occur in cancer and can drive cellular growth and tumor progression.
These findings highlight the potential of targeting ERBB4 with pan-ERBB inhibitors for specific cancer patient populations.