Chemogenomic profiling of breast cancer patient-derived xenografts reveals targetable vulnerabilities for difficult-to-treat tumors.

Paul Savage, Alain Pacis, Hellen Kuasne, Leah Liu, Daniel Lai, Adrian Wan, Matthew Dankner, Constanza Martinez, Valentina Muñoz-Ramos, Virginie Pilon, Anie Monast, Hong Zhao, Margarita Souleimanova, Matthew G Annis, Adriana Aguilar-Mahecha, Josiane Lafleur, Nicholas R Bertos, Jamil Asselah, Nathaniel Bouganim, Kevin Petrecca, Peter M Siegel, Atilla Omeroglu, Sohrab P Shah, Samuel Aparicio, Mark Basik, Sarkis Meterissian, Morag Park, Communications biology 3, 310 (2020)
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Subsets of breast tumors present major clinical challenges, including triple-negative, metastatic/recurrent disease and rare histologies. Here, we developed 37 patient-derived xenografts (PDX) from these difficult-to-treat cancers to interrogate their molecular composition and functional biology. Whole-genome and transcriptome sequencing and reverse-phase protein arrays revealed that PDXs conserve the molecular landscape of their corresponding patient tumors. Metastatic potential varied between PDXs, where low-penetrance lung micrometastases were most common, though a subset of models displayed high rates of dissemination in organotropic or diffuse patterns consistent with what was observed clinically. Chemosensitivity profiling was performed in vivo with standard-of-care agents, where multi-drug chemoresistance was retained upon xenotransplantation. Consolidating chemogenomic data identified actionable features in the majority of PDXs, and marked regressions were observed in a subset that was evaluated in vivo. Together, this clinically-annotated PDX library with comprehensive molecular and phenotypic profiling serves as a resource for preclinical studies on difficult-to-treat breast tumors.