Dataset Information

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

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.

SUBMITTER: Savage P

PROVIDER: S-EPMC7298048 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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

Savage Paul P Pacis Alain A Kuasne Hellen H Liu Leah L Lai Daniel D Wan Adrian A Dankner Matthew M Martinez Constanza C Muñoz-Ramos Valentina V Pilon Virginie V Monast Anie A Zhao Hong H Souleimanova Margarita M Annis Matthew G MG Aguilar-Mahecha Adriana A Lafleur Josiane J Bertos Nicholas R NR Asselah Jamil J Bouganim Nathaniel N Petrecca Kevin K Siegel Peter M PM Omeroglu Atilla A Shah Sohrab P SP Aparicio Samuel S Basik Mark M Meterissian Sarkis S Park Morag M

Communications biology 20200616 1

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 ...[more]

PMID: 32546838

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Project description:Breast cancer is a heterogeneous collection of disease arising from the breast with distinct molecular and phenotypic features. Certain subsets of patients have tumors that are particularly difficult-to-treat, which include triple-negative breast cancer (TNBC), metastatic/recurrent disease and rare histological variants. To delineate the underlying biology and identify therapeutic candidates for these patients, a series of 37 breast cancer patient-derived xenografts (PDX) from both chemo-naïve and pre-treated specimens was generated from 81 transplant attempts. Whole-genome and transcriptome sequencing revealed marked fidelity of the molecular landscape for the majority of PDXs in comparison to parental tumors. Reverse-phase protein array analysis of PDXs further identified potential therapeutic targets. Metastatic potential varied between PDXs, where low-penetrance lung micrometastases was the most common pattern of dissemination and observed in 34.5% of models. Three PDXs recapitulated the metastatic localization seen in the corresponding patients, including two lines with high-frequency metastases to multiple vital organ systems, while another PDX displayed tropism to the skull-base. Chemosensitivity profiling was performed in vivo with standard-of-care agents (doxorubicin, cisplatin, gemcitabine or paclitaxel), where multi-drug chemoresistance was found in 60.0% of PDXs and 64.7% of responses were concordant with pre-engraftment responses observed in the patient. Consolidating chemogenomic data identified potentially actionable features in 97.2% of PDXs, and marked regressions were seen in vivo when a subset of these underwent proof-of-concept functional studies. This included FGFR inhibitor sensitivity in a FGFR1-amplified lobular carcinoma, mTOR inhibitor sensitivity in a recurrent neuroendocrine breast cancer with proteomic evidence of mTOR/PI3K activation, and platinum sensitivity in a TNBC with BRCA1 germline mutation predicted as benign. Together, this clinically-annotated PDX library with comprehensive molecular and phenotypic profiling serves as a resource for both discovery and validation preclinical studies on difficult-to-treat breast tumors.

Dataset Information

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

Publications

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

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