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Updated: Jun 25, 2025

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Trans-activating mutations of the pseudokinase ERBB3

Marika K A Koivu1,2,3, Deepankar Chakroborty1,2,3, Tomi T Airenne4

  • 1Institute of Biomedicine, and Medicity Research Laboratories, University of Turku, Turku, 20520, Finland.

Oncogene
|May 28, 2024
PubMed

Insights

This study screened thousands of ERBB3 mutations, identifying 18 that drive cancer. These ERBB3 variants show potential for targeted therapies with existing ERBB inhibitor drugs.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • ERBB family receptor tyrosine kinases are crucial in cancer, with ERBB3 being a pseudokinase known for signaling via ERBB2 heterodimers.
  • Most somatic ERBB3 variants found in cancers have unknown significance, hindering targeted therapy development.

Purpose of the Study:

  • To conduct an unbiased functional genetics screen to identify transforming ERBB3 mutations.
  • To assess the oncogenic potential of ERBB3 variants and their implications for targeted therapies.

Main Methods:

  • Utilized the iSCREAM (in vitro screen of activating mutations) platform for parallel screening of thousands of ERBB3 mutations.
  • Validated identified mutations in Ba/F3, NIH 3T3, and MCF10A cell lines, assessing both single variants and pairwise combinations.
  • Performed drug sensitivity assays using trastuzumab, pertuzumab, and neratinib.

Main Results:

  • Identified 18 ERBB3 mutations with transforming potential.
  • Confirmed both known and novel transforming ERBB3 missense mutations, functioning individually or in cis.
  • Demonstrated that these transforming ERBB3 variants are actionable with specific ERBB inhibitor drugs.

Conclusions:

  • This comprehensive screen reveals novel insights into ERBB3 oncogenic drivers.
  • Identified ERBB3 variants represent potential biomarkers for ERBB inhibitor therapies, offering new avenues for cancer treatment.

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