Reference Detail

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.

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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
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 results in increased Erbb4 phosphorylation and IL-3 independent growth in the presence of ligand in one cell line but did not show anchorage-independent growth in another cell line 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 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 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 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 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
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 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 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 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	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	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 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	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