A1 Refereed original research article in a scientific journal
Trans-activating mutations of the pseudokinase ERBB3
Authors: Koivu, Marika K. A.; Chakroborty, Deepankar; Airenne, Tomi T.; Johnson, Mark S.; Kurppa, Kari J.; Elenius, Klaus
Publisher: Springer Nature
Publication year: 2024
Journal: Oncogene
Journal name in source: Oncogene
Journal acronym: Oncogene
Volume: 43
First page : 2253
Last page: 2265
ISSN: 0950-9232
eISSN: 1476-5594
DOI: https://doi.org/10.1038/s41388-024-03070-9
Web address : https://www.nature.com/articles/s41388-024-03070-9
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/454735859
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.
Downloadable publication This is an electronic reprint of the original article. |  |
Funding information in the publication:
Open Access funding provided by University of Turku (including Turku University Central Hospital).
