HER2 as a therapeutic target in bladder cancer

Background: HER2 (encoded by the ERBB2 gene) is a non-ligand-binding member of this family that exerts its activity through homo- or heterodimerization with other ERBB proteins. While multiple HER2-targeted therapies are FDA-approved for breast cancer, clinical utility targeting in bladder cancer patients remains undefined. Therefore, we leveraged prospective sequencing initiative and new collection patient-derived organoid (PDO) xenograft (PDX) models to explore prevalence biologic role pathogenesis potential therapies. Material methods: To define landscape alterations patients, data generated The Cancer Genome Atlas (TCGA), 2230 enrolled tumor genomic profiling at Memorial Sloan Kettering Center (MSK). We 41 PDOs genetically phenotypically reflect human disease. Those proprietary were characterized various used understand activation sensitivity anti-HER2 targeted agents. Results: 17% TCGA 16% MSK cohorts had oncogenic mutations and/or gene amplification. more common tumors higher grade stage, also varied significantly as function histology highest frequency micropapillary subtype (37% vs 19% UC, NOS). Analysis 119 paired primary/metastatic noted discordance 37.5% alterations. Compared mean copy number amplified cancers was lower (2.69 3.30, p-value = 0.004), correlation between linear mRNA expression. Of PDX/PDO models, identified 10. altered PDX sensitive antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) than HER kinase inhibitor neratinib. Neratinib resistance associated lacking AKT dependence on upstream activation. Conclusion: In sum, mutations/amplification stage enriched histology. addition, observed frequent status pairs expression versus cancers. Preclinical evaluation PDO/PDXs indicated greater HER2-directed ADC T-DXd compared neratinib, which provided justification trials ADCs patients. Conflict interest: Advisory Board: D.B.S. has served consultant for/received honorarium from Pfizer, Loxo/Lilly Oncology, Vividion Therapeutics, Scorpion Fore Therapeutics BridgeBio. H.A.A consultation AstraZeneca, Janssen Biotech, Bristol-Myers-Squibb Paige.ai. M.B. Eli Lilly PetDx.