Abstract 3988: Identification of HER4 mutations with potential as biomarkers of response to neratinib
Authors: Valenti Marta , Conlon Neil T. , Eli Lisa D. , Diala Irmina , Crown John , Collins Denis M. 
Published: June 2022

Background: HER4 is a member of the human epidermal growth factor receptor (HER/ErbB) family of receptor tyrosine kinases. HER4 is activated through ligand binding, transmitting intracellular signals by homodimerizing, or by heterodimerizing with other family members (EGFR, HER2, HER3). The role of HER4 in cancer or normal tissue has not been studied as comprehensively as EGFR and HER2, potentially due to a more complex biology that includes four different isoforms and different stability/tissue-specific expression patterns, and oncogenic or oncosuppressor roles. The oral, irreversible pan-HER (EGFR, HER2, HER4) tyrosine kinase inhibitor (TKI) neratinib (NER) is clinically active against HER2-mutant and HER2-amplified cancers. Using publicly available datasets including cBioPortal and COSMIC and predicted structural and functional impacts, this study aimed to identify HER4 mutations with the greatest oncogenic potential that may have value as potential biomarkers of response to NER.

Methods: The frequency of HER4 mutations across 33 cancer types was determined by using the clinical database cBioPortal and TCGA PanCancer Atlas datasets (n=10967). A shortlist of potentially oncogenic HER4 mutations was created based on the occurrence in cBioPortal and COSMIC databases, annotation as putative driver and cancer hotspot, structural and functional impacts according to OncoKB, Mutation Assessor, SIFT and Polyphen-2 software, and HER4 protein folding studies. Analysis was carried out using the R-studio statistical environment.

Results: HER4 amplification is rare in cancer, with the majority of genetic changes reported as point mutations; particularly missense (31.93%), synonymous (6.43%) and nonsense (3%) substitutions. Melanoma and esophagogastric (EG) cancers showed the highest HER4 alteration frequency, 17.34% and 13.42%, respectively, across different cancer types in the cBioPortal database. Melanoma and EG cancers showed the second and third highest absolute count of HER4 genomic alterations (n=77 and n=69, respectively). Based on the criteria outlined in methods, a priority list of HER4 mutations with greatest oncogenic potential was curated for melanoma (HER4 R106C, R306C, R711C, G936E, F1003I), stomach (HER4 C217R, S774N, K1002R, Y1150C) and esophageal (HER4 R488W, S449Y) adenocarcinomas. Mutations at these sites, located across ligand-binding, dimerization and intracellular signaling domains, have the potential to impact HER4 activity and thus possibly act as biomarkers of response to an irreversible pan-HER TKI like NER.

Conclusions: These data suggest that melanoma and EG cancers are the cancer types with the highest rate of HER4 mutations. In vitro functional characterization of the identified HER4 mutations is now required to further explore their value as biomarkers of response to NER.

Citation Format: Marta Valenti, Neil T. Conlon, Lisa D. Eli, Irmina Diala, John Crown, Denis M. Collins. Identification of HER4 mutations with potential as biomarkers of response to neratinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3988.