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

• DOI: 10.1038/s42003-020-1042-x
• Publication Date: 2020-06-16T10:03:58Z
• Authors: Paul Savage; Alain Pacis; Hellen Kuasne; Leah Liu; Daniel Lai; Adrian Wan; Matthew Dankner; Constanza Martinez; Valentina Muñoz-R...; Virginie Pilon; Anie Monast; Hong Zhao; Margarita Souleim...; Matthew G. Annis; Adriana Aguilar-M...; 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
• Keywords: Xenotransplantation

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 functional biology. Whole-genome transcriptome sequencing reverse-phase protein arrays revealed that PDXs conserve the landscape corresponding patient tumors. Metastatic potential varied between PDXs, where low-penetrance lung micrometastases were most common, though a subset models displayed high rates dissemination in organotropic or diffuse patterns consistent with what was observed clinically. Chemosensitivity profiling performed vivo standard-of-care agents, multi-drug chemoresistance retained upon xenotransplantation. Consolidating chemogenomic data identified actionable features majority marked regressions evaluated vivo. Together, this clinically-annotated PDX library comprehensive phenotypic serves as resource for preclinical studies on