biostudies-literatureUnknown13Schubert L<h4>Purpose</h4>Gene fusions involving receptor tyrosine kinases (RTKs) define an important class of genomic alterations with many successful targeted therapies now approved for <i>ALK</i>, <i>ROS1</i>, <i>RET</i> and <i>NTRK</i> gene fusions. Fusions involving the <i>ERBB</i> family of RTKs have been sporadically reported, but their frequency has not yet been comprehensively analyzed and functional characterization is lacking on many types of <i>ERBB</i> fusions.<h4>Materials and methods</h4>We analyzed tumor samples submitted to Caris Life Sciences (n=64,354), as well as the TCGA (n=10,967), MSK IMPACT (n=10,945) and AACR GENIE (n=96,324) databases for evidence of <i>EGFR, ERBB2</i> and <i>ERBB4</i> gene fusions. We also expressed several novel fusions in cancer cell lines and analyzed their response to EGFR and HER2 tyrosine kinase inhibitors (TKIs).<h4>Results</h4>In total, we identified 1,251 <i>ERBB</i> family fusions, representing an incidence of approximately 0.7% across all cancer types. <i>EGFR, ERBB2</i>, and <i>ERBB4</i> fusions were most frequently found in glioblastoma, breast cancer and ovarian cancer, respectively. We modeled two novel types of <i>EGFR</i> and <i>ERBB2</i> fusions, one with a tethered kinase domain and the other with a tethered adapter protein. Specifically, we expressed <i>EGFR-ERBB4, EGFR-SHC1, ERBB2-GRB7</i> and <i>ERBB2-SHC1</i>, in cancer cell lines and demonstrated that they are oncogenic, regulate downstream signaling and are sensitive to small molecule inhibition with EGFR and HER2 TKIs.<h4>Conclusions</h4>We found that <i>ERBB</i> fusions are recurrent mutations that occur across multiple cancer types. We also establish that adapter-tethered and kinase-tethered fusions are oncogenic and can be inhibited with EGFR or HER2 inhibitors. We further propose a nomenclature system to categorize these fusions into several functional classes.Frontiers in oncology1115405https://www.ebi.ac.uk/biostudies/studies/S-EPMC10164992biostudies-literature<i>ERBB</i> family fusions are recurrent and actionable oncogenic targets across cancer types.PMC10164992Korn WMEl-Deiry WSBraxton DRBorghaei HLiu SVLe ATEstrada-Bernal ALou EThomas CAKurzrock RSchubert LDoebele RCElliott ADemeure MJOu SIReuss JEDarabi Sfalse<i>ERBB</i> family fusions are recurrent and actionable oncogenic targets across cancer types.<h4>Purpose</h4>Gene fusions involving receptor tyrosine kinases (RTKs) define an important class of genomic alterations with many successful targeted therapies now approved for <i>ALK</i>, <i>ROS1</i>, <i>RET</i> and <i>NTRK</i> gene fusions. Fusions involving the <i>ERBB</i> family of RTKs have been sporadically reported, but their frequency has not yet been comprehensively analyzed and functional characterization is lacking on many types of <i>ERBB</i> fusions.<h4>Materials and methods</h4>We analyzed tumor samples submitted to Caris Life Sciences (n=64,354), as well as the TCGA (n=10,967), MSK IMPACT (n=10,945) and AACR GENIE (n=96,324) databases for evidence of <i>EGFR, ERBB2</i> and <i>ERBB4</i> gene fusions. We also expressed several novel fusions in cancer cell lines and analyzed their response to EGFR and HER2 tyrosine kinase inhibitors (TKIs).<h4>Results</h4>In total, we identified 1,251 <i>ERBB</i> family fusions, representing an incidence of approximately 0.7% across all cancer types. <i>EGFR, ERBB2</i>, and <i>ERBB4</i> fusions were most frequently found in glioblastoma, breast cancer and ovarian cancer, respectively. We modeled two novel types of <i>EGFR</i> and <i>ERBB2</i> fusions, one with a tethered kinase domain and the other with a tethered adapter protein. Specifically, we expressed <i>EGFR-ERBB4, EGFR-SHC1, ERBB2-GRB7</i> and <i>ERBB2-SHC1</i>, in cancer cell lines and demonstrated that they are oncogenic, regulate downstream signaling and are sensitive to small molecule inhibition with EGFR and HER2 TKIs.<h4>Conclusions</h4>We found that <i>ERBB</i> fusions are recurrent mutations that occur across multiple cancer types. We also establish that adapter-tethered and kinase-tethered fusions are oncogenic and can be inhibited with EGFR or HER2 inhibitors. We further propose a nomenclature system to categorize these fusions into several functional classes.2023-01-01T00:00:00Z20232025-04-05T10:54:42.52Z2025-04-05T10:54:42.52ZS-EPMC101649923716836510.3389/fonc.2023.1115405