Reference Detail

Request Content

Contact

Missing content? – Request curation!

Request curation for specific Genes, Variants, or PubMed publications.

Have questions, comments, or suggestions? - Let us know!

Email us at : ckbsupport@genomenon.com

Ref Type Journal Article
PMID (36860695)
Authors Chakroborty D, Ojala VK, Knittle AM, Drexler J, Tamirat MZ, Ruzicka R, Bosch K, Woertl J, Schmittner S, Elo LL, Johnson MS, Kurppa KJ, Solca F, Elenius K
Title An Unbiased Functional Genetics Screen Identifies Rare Activating ERBB4 Mutations.
Journal Vol Issue Date Pages Journal Short Title
Cancer research communications 2 1 2022 Jan 10-27 Cancer Res Commun
URL
Abstract Text 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.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.

Filtering

  • Case insensitive filtering will display rows if any text in any cell matches the filter term
  • Use simple literal full or partial string matches
  • Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
  • Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

  • Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
ERBB4 E715K missense gain of function ERBB4 E715K lies within the cytoplasmic domain of the Erbb4 protein (UniProt.org). E715K results in anchorage-independent growth and increased Erbb4 phosphorylation in culture and induced tumor growth in mouse models (PMID: 36860695).
ERBB4 G741R missense gain of function - predicted ERBB4 G741R lies within the protein kinase domain of the Erbb4 protein (UniProt.org). G741R did not show anchorage-independent growth in one cell line in culture but results in increased Erbb4 phosphorylation and IL-3 independent growth in the presence of ligand in culture (PMID: 36860695), and therefore, is predicted to lead to a gain of Erbb4 protein function.
ERBB4 G802D missense gain of function ERBB4 G802D lies within the protein kinase domain of the Erbb4 protein (UniProt.org). G802D confers a gain of Erbb4 protein function as demonstrated by anchorage-independent growth in the presence of ligand and increased Erbb4 phosphorylation in culture (PMID: 36860695).
ERBB4 M993I missense gain of function - predicted ERBB4 M993I lies within the cytoplasmic domain of the Erbb4 protein (UniProt.org). M993I results in anchorage-independent growth in the presence of ligand but similar phosphorylation to wild-type Erbb4 in culture (PMID: 36860695), and therefore, is predicted to lead to a gain of Erbb4 protein function.
ERBB4 R687K missense gain of function ERBB4 R687K lies within the cytoplasmic domain of the Erbb4 protein (UniProt.org). R687K results in anchorage-independent growth and increased Erbb4 phosphorylation in cultured cells (PMID: 36860695).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ERBB4 E715K Advanced Solid Tumor sensitive Afatinib Preclinical - Cell culture Actionable In a preclinical study, Gilotrif (afatinib) inhibited growth of a transformed cell line expressing ERBB4 E715K in culture (PMID: 36860695). 36860695
ERBB4 G741R Advanced Solid Tumor sensitive Neratinib Preclinical - Cell culture Actionable In a preclinical study, Nerlynx (neratinib) inhibited growth of a transformed cell line expressing ERBB4 G741R in culture (PMID: 36860695). 36860695
ERBB4 G741R Advanced Solid Tumor sensitive Afatinib Preclinical - Cell culture Actionable In a preclinical study, Gilotrif (afatinib) inhibited growth of a transformed cell line expressing ERBB4 G741R in culture (PMID: 36860695). 36860695
ERBB4 R687K Advanced Solid Tumor sensitive Afatinib Preclinical - Cell culture Actionable In a preclinical study, Gilotrif (afatinib) inhibited growth of a transformed cell line expressing ERBB4 R687K in culture (PMID: 36860695). 36860695
ERBB4 R687K Advanced Solid Tumor sensitive Neratinib Preclinical - Cell culture Actionable In a preclinical study, Nerlynx (neratinib) inhibited growth of a transformed cell line expressing ERBB4 R687K in culture (PMID: 36860695). 36860695
ERBB4 E715K Advanced Solid Tumor sensitive Dacomitinib Preclinical - Cell culture Actionable In a preclinical study, Vizimpro (dacomitinib) inhibited growth of a transformed cell line expressing ERBB4 E715K in culture (PMID: 36860695). 36860695
ERBB4 G741R Advanced Solid Tumor resistant Erlotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing ERBB4 G741R were resistant to Tarceva (erlotinib) treatment in culture (PMID: 36860695). 36860695
ERBB4 R687K Advanced Solid Tumor resistant Erlotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing ERBB4 R687K were resistant to Tarceva (erlotinib) treatment in culture (PMID: 36860695). 36860695
ERBB4 E715K Advanced Solid Tumor resistant Erlotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing ERBB4 E715K were resistant to Tarceva (erlotinib) treatment in culture (PMID: 36860695). 36860695
ERBB4 E715K Advanced Solid Tumor sensitive Neratinib Preclinical - Cell culture Actionable In a preclinical study, Nerlynx (neratinib) inhibited growth of a transformed cell line expressing ERBB4 E715K in culture (PMID: 36860695). 36860695
ERBB4 G741R Advanced Solid Tumor sensitive Dacomitinib Preclinical - Cell culture Actionable In a preclinical study, Vizimpro (dacomitinib) inhibited growth of a transformed cell line expressing ERBB4 G741R in culture (PMID: 36860695). 36860695
ERBB4 R687K Advanced Solid Tumor sensitive Dacomitinib Preclinical - Cell culture Actionable In a preclinical study, Vizimpro (dacomitinib) inhibited growth of a transformed cell line expressing ERBB4 R687K in culture (PMID: 36860695). 36860695