Genomic profiling of a multi-lineage and multi-passage patient-derived xenograft biobank reflects heterogeneity of ovarian cancer

Ovarian cancer (OC) manifests as a complex disease characterized by inter- and intra-patient heterogeneity. Despite enhanced biological and genetic insights, OC remains a recalcitrant malignancy with minimal survival improvement. Based on multi-site sampling and a multi-lineage patient-derived xenograft (PDX) establishment strategy, we present herein the establishment of a comprehensive PDX biobank from histologically and molecularly heterogeneous OC patients. Comprehensive profiling of matched PDX and patient samples demonstrates that PDXs closely recapitulate parental tumors. By leveraging multi-lineage models, we reveal that the previously reported genomic disparities of PDX could be mainly attributed to intra-patient spatial heterogeneity instead of substantial model-independent genomic evolution. Moreover, DNA damage response pathway inhibitor (DDRi) screening uncovers heterogeneous responses across models. Prolonged iterative drug exposure recapitulates acquired drug resistance in initially sensitive models. Meanwhile, interrogation of induced drug-resistant (IDR) models reveals that suppressed interferon (IFN) response and activated Wnt/β-catenin signaling contribute to acquired DDRi drug resistance. [Display omitted] •Establishment of a PDX biobank from histologically and molecularly heterogeneous OC•Multi-lineage and multi-passage PDX analysis reveals model fidelity•Intra-patient spatial heterogeneity contributes to genomic disparities in PDX model•Prolonged iterative exposure recapitulates drug resistance in PDX models in vivo Qin et al. present an ovarian cancer PDX biobank consisting of 66 distinctive lineages derived from 53 patients. Histological, genetic, and phylogenetic analyses of multi-lineage and multi-passage PDXs, in conjunction with multi-site patient tumors, demonstrate the biobank’s fidelity. Generation and interrogation of induced drug-resistant PDXs reveal DDR inhibitor resistance mechanisms.