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Trans-activating mutations of the pseudokinase ERBB3. | LitMetric

Trans-activating mutations of the pseudokinase ERBB3.

Oncogene

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

Published: July 2024

AI Article Synopsis

  • The ERBB family of receptor tyrosine kinases plays a critical role in cancer development, with ERBB3 being a significant player despite having a non-active kinase domain; its mutations can impact treatment responses to ERBB inhibitors.* -
  • Researchers conducted a comprehensive study using the iSCREAM platform to explore thousands of ERBB3 mutations, identifying 18 mutations that can transform cancer cells, including both previously known and novel variants.* -
  • Functional tests showed that the newly identified ERBB3 mutations can influence drug effectiveness, suggesting that these mutations may serve as useful biomarkers for therapies like trastuzumab, pertuzumab, and neratinib.*

Article Abstract

Genetic changes in the ERBB family of receptor tyrosine kinases serve as oncogenic driver events and predictive biomarkers for ERBB inhibitor drugs. ERBB3 is a pseudokinase member of the family that, although lacking a fully active kinase domain, is well known for its potent signaling activity as a heterodimeric complex with ERBB2. Previous studies have identified few transforming ERBB3 mutations while the great majority of the hundreds of different somatic ERBB3 variants observed in different cancer types remain of unknown significance. Here, we describe an unbiased functional genetics screen of the transforming potential of thousands of ERBB3 mutations in parallel. The screen based on a previously described iSCREAM (in vitro screen of activating mutations) platform, and addressing ERBB3 pseudokinase signaling in a context of ERBB3/ERBB2 heterodimers, identified 18 hit mutations. Validation experiments in Ba/F3, NIH 3T3, and MCF10A cell backgrounds demonstrated the presence of both previously known and unknown transforming ERBB3 missense mutations functioning either as single variants or in cis as a pairwise combination. Drug sensitivity assays with trastuzumab, pertuzumab and neratinib indicated actionability of the transforming ERBB3 variants.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11245391PMC
http://dx.doi.org/10.1038/s41388-024-03070-9DOI Listing

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