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 Martínez, Valentina Muñoz-Ramos, Virginie Pilon, Anie Monast, Hong Zhao, Margarita Souleimanova, Matthew G. Annis, Adriana Aguilar‐Mahecha, Josiane Lafleur, Nicholas Bertos, Jamil Asselah, Nathaniel Bouganim, Kevin Petrecca, Peter M. Siegel, Atilla Ömeroğlu, Sohrab P. Shah, Samuel Aparício, Mark Basik, Sarkis Meterissian, Morag Park
Abstract
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.