Abstract 4761: The ERBB4 exon skipping isoform JMA-CYT2 is the dominant isoform of ERBB4 gene fusions

Abstract Background: ERBB4, a member of the ERBB family of receptor tyrosine kinases, has received less attention than its counterparts, ERBB1 (EGFR), ERBB2 (HER2) and ERBB3(HER3), despite its established involvement in oncogenesis and its potential as a therapeutic target. While the role of ERBB4 and its isoforms in neuronal development is well understood, mutations and fusions of ERBB4 have been linked to several types of cancer, however they have not been fully explored. Further research into ERBB4 fusions and their oncogenic mechanisms is essential for advancing targeted therapies. Methods: We performed a comprehensive analysis of ERBB4 fusions using next-generation sequencing (NGS) data from a total of 216, 176 formalin-fixed paraffin-embedded (FFPE) tumor samples across various solid tumors. NGS was conducted on DNA isolated from these samples and RNA fusions were detected using whole transcriptome sequencing (WTS). We analyzed patient demographics, fusion partners, ERBB4 isoforms, and co-occurring mutations. Additionally, tumor mutational burden (TMB) was assessed, and data from public bioinformatic resources were used for comparison. Results: ERBB4 fusions were detected in 0.25% of the 24 solid tumor types analyzed, with the highest prevalence observed in OSEC, BRCA, BLCA, UTNE, and NSCLC. Notably, 63.1% of ERBB4 fusions involved the 3' end of the gene and included various fusion partners. The most common fusion partner was IKZF2:ERBB4, accounting for 58.2% of cases. Exon 2 was identified as the most frequent breakpoint in ERBB4 fusions. As a result, 5' ERBB4 fusions retain only the signal peptide, while 3' fusions lose the signal peptide, which may impair translocation to the cell membrane. The most common isoform observed in ERBB4 fusions was the JMa-Cyt2 isoform, seen in over 83% of cases. This isoform skips exon 26, which contains a PI3K phosphorylation site critical for ubiquitination and degradation. Further analyses revealed a significant upregulation of ERBB4 expression in ERBB4 fusion positive cases in BLCA(P>0.001), OSEC(P>0.001), and NSCLC(P>0.001). Pathway analyses revealed upregulation of Myc targets indicating ERBB4-ICD-STAT5A complex in promoting cell proliferation. Co-occurring mutations are enriched in TP53, PIK3CA, and TERT in ERBB4 fusions. Conclusion: Our study highlights the frequent occurrence of ERBB4 fusions across various cancer types, with IKZF2 being the most common fusion partner. The prevalence of the ubiquitination-resistant JMa-Cyt2 isoform and the retention of cytoplasmic (kinase) domain in many fusions suggest that ERBB4 fusions may contribute to oncogenesis through a STAT5A-dependent mechanism, independent of PI3K. These findings underscore the potential of ERBB4 fusions as therapeutic targets and suggest that gamma-secretase inhibitors could be a promising treatment option for patients with these fusions. Citation Format: Shivani Jagannathan Murali, Bharath Kumar Karre, Cristina Ivan, Chao Sima, Asfetaw Abera, David Spetzler, Milan Radovich, Heather O'neill, Ravi Chakra Turaga. The ERBB4 exon skipping isoform JMA-CYT2 is the dominant isoform of ERBB4 gene fusions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4761.