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| Status |
Public on Dec 31, 2019 |
| Title |
Chemogenomic profiling of breast cancer patient-derived xenografts reveals targetable vulnerabilities for difficult-to-treat tumors |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
RNA sequencing data from breast cancer pairs of primary tumors and PDXs.
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| Contributor(s) |
Savage P, Pacis A, Kuasne H, Liu L, Lai D, Wan A, Muñoz-Ramos V, Pilon V, Monast A, Zhao H, Souleimanova M, Dankner MG, Annis M, Aguilar-Mahecha A, Bertos NR, Asselah J, Bouganim N, Petrecca K, Siegel PM, Omeroglu A, Shah SP, Aparicio S, Basik M, Meterissian S, Park M |
| Citation(s) |
32546838 |
| Submission date |
Dec 30, 2019 |
| Last update date |
Jul 21, 2020 |
| Contact name |
Alain Pacis |
| E-mail(s) |
alain.pacis@mcgill.ca
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| Organization name |
Canadian Centre for Computational Genomics (C3G)
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| Street address |
740 Dr Penfield Ave
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| City |
Montreal |
| State/province |
QC |
| ZIP/Postal code |
H3A 0G1 |
| Country |
Canada |
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| Platforms (1) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
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| Samples (66)
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| Relations |
| BioProject |
PRJNA598222 |
| SRA |
SRP239118 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE142767_RAW.tar |
13.2 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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