DDDR-21. Characterizing novel patient-derived breast cancer brain metastases models through high-throughput drug screening and integrative omics profiling

Abstract The development of breast cancer brain metastases (BCBM) is among the most critical predictive factors for patient survival. However, understanding the drug sensitivity of BCBM cells to various drugs, particularly in terms of how effectively they eliminate specific tumor cell clones responsible for the disease, remains limited. Acquiring this knowledge is crucial for improving drug selection and personalizing treatment strategies for individual patients. For this purpose, we generated novel patient-derived BCBM cell lines from three individuals with triple-negative breast cancer and three with HER2-enriched breast cancer. Whole genome and transcriptome analyses verified their resemblance to the original tumor tissues. We performed high-throughput drug screening to evaluate responses to over 250 drugs, testing more than 10 dosage points within our framework HeiDePEx (Heidelberg Drug Screening Platform for Experimental Neurosurgery). The findings were further explored in relation to patient-matched multi-omics data generated as part of the CATCH study, a metastatic breast cancer precision oncology program, which integrates drug screening results, clinical data, and molecular information. Overall, the newly established BCBM cell lines exhibited drug responses that closely reflected the individual patient and breast cancer subtype. Furthermore, they enhanced the clinically assessed multi-omics data by providing extensive insights into functional cellular vulnerabilities across a wide range of targeted anticancer drugs. Taken together, these findings emphasize the critical importance of personalized therapeutic strategies for BCBM patients and demonstrate the value of integrating functional drug screening with multi-omics data. Ultimately, the newly developed and characterized BCBM cell lines serve as a valuable resource for future research.