Neratinib Synergizes with Trastuzumab Antibody Drug Conjugate or with Vinorelbine to Treat HER2 Mutated Breast Cancer Patient Derived Xenografts and Organoids.

HER2 (ERBB2) is a major therapeutic drug target in breast cancer and The Cancer Genome Atlas (TCGA) Breast Cancer project and other studies have identified HER2 activating mutations in breast cancers without HER2 gene amplification. HER2 activating mutations occur in 2-5% of metastatic breast cancer patients (MBC), and clinical trials have shown that the irreversible pan-HER tyrosine kinase inhibitor, neratinib, produces a 31-40% clinical benefit rate for HER2 mutated MBC patients. We developed breast cancer patient-derived xenografts (PDX) from ER+, HER2 mutated MBC patients and used them to test neratinib-based drug combinations. Using organoid culture of these PDX breast cancer cells, we performed rapid, high-throughput ex vivo screening assays to test novel drug combinations. These organoid culture experiments identified drug synergy with the neratinib plus ado-trastuzumab emtansine (T-DM1) and neratinib plus vinorelbine combinations and we validated these results with in vivo PDX experiments. ### Competing Interest Statement S. Li receives license fees from Horizon Discovery for several WHIM PDX lines. L.D. Eli is an employee of Puma Biotechnology. C. Ma is the PI for an Investigator-Initiated Clinical Trial funded by Puma Biotechnology, served on the advisory board or performed consulting for AstraZeneca, Novartis, Tempus, Pfizer, Eli Lilly, Diiichi, Stemline, Novartis, and Seattle Genetics, TerSera, Sanofi, Olaris, Merck, and received research funding from Puma Biotechnology and Pfizer. R. Bose receives research funding from Puma Biotechnology and performs consulting for Genentech.