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An Unbiased Functional Genetics Screen Identifies Rare Activating ERBB4 Mutations
Deepankar Chakroborty1,2,3,4, Veera K Ojala1,2,3,4, Anna M Knittle1
1Institute of Biomedicine, University of Turku, Turku, Finland.
Abstract:
Despite the relatively high frequency of somatic ERBB4 mutations in various cancer types, only a few activating ERBB4 mutations have been characterized, primarily due to lack of mutational hotspots in the ERBB4 gene. Here, we utilized our previously published pipeline, an in vitro screen for activating mutations, to perform an unbiased functional screen to identify potential activating ERBB4 mutations from a randomly mutated ERBB4 expression library. Ten potentially activating ERBB4 mutations were identified and subjected to validation by functional and structural analyses. Two of the 10 ERBB4 mutants, E715K and R687K, demonstrated hyperactivity in all tested cell models and promoted cellular growth under two-dimensional and three-dimensional culture conditions. ERBB4 E715K also promoted tumor growth in in vivo Ba/F3 cell mouse allografts. Importantly, all tested ERBB4 mutants were sensitive to the pan-ERBB tyrosine kinase inhibitors afatinib, neratinib, and dacomitinib. Our data indicate that rare ERBB4 mutations are potential candidates for ERBB4-targeted therapy with pan-ERBB inhibitors.
Statement Of Significance:
ERBB4 is a member of the ERBB family of oncogenes that is frequently mutated in different cancer types but the functional impact of its somatic mutations remains unknown. Here, we have analyzed the function of over 8,000 randomly mutated ERBB4 variants in an unbiased functional genetics screen. The data indicate the presence of rare activating ERBB4 mutations in cancer, with potential to be targeted with clinically approved pan-ERBB inhibitors.
Insights
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.
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.
