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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. | ||||||||||||
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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. |
Molecular Profile | Treatment Approach |
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Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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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 |
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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 |