A population of heterogeneous breast cancer patient-derived xenografts demonstrate broad activity of PARP inhibitor in BRCA1/2 wild-type tumors

Kurt W. Evans, Erkan Yuca, Argun Akcakanat, Stephen M. Scott, Natalia Paez Arango, Xiaofeng Zheng, Ken Chen, Coya Tapia, Emily Tarco, Agda K. Eterovic, Dalliah M. Black, Jennifer K. Litton, Timothy A. Yap, Debu Tripathy, Gordon B. Mills, Funda Meric-Bernstam

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Background: Breast cancer patients who do not respond to neoadjuvant therapy have a poor prognosis. There is a pressing need for novel targets and models for preclinical testing. Here we report characterization of breast cancer patient-derived xenografts (PDX) largely generated from residual tumors following neoadjuvant chemotherapy. Experimental Design: PDXs were derived from surgical samples of primary or locally recurrent tumors. Normal and tumor DNA sequencing, RNASeq, and reverse phase protein arrays (RPPA) were performed. Phenotypic profiling was performed by determining efficacy of a panel of standard and investigational agents. Results: Twenty-six PDXs were developed from 25 patients. Twenty-two were generated from residual disease following neoadjuvant chemotherapy, and 24 were from triple-negative breast cancer (TNBC). These PDXs harbored a heterogeneous set of genomic alterations and represented all TNBC molecular subtypes. On RPPA, PDXs varied in extent of PI3K and MAPK activation. PDXs also varied in their sensitivity to chemotherapeutic agents. PI3K, mTOR, and MEK inhibitors repressed growth but did not cause tumor regression. The PARP inhibitor talazoparib caused dramatic regression in five of 12 PDXs. Notably, four of five talazoparib-sensitive models did not harbor germline BRCA1/2 mutations, but several had somatic alterations in homologous repair pathways, including ATM deletion and BRCA2 alterations. Conclusions: PDXs capture the molecular and phenotypic heterogeneity of TNBC. Here we show that PARP inhibition can have activity beyond germline BRCA1/2 altered tumors, causing regression in a variety of molecular subtypes. These models represent an opportunity for the discovery of rational combinations with targeted therapies and predictive biomarkers.

Original languageEnglish (US)
Pages (from-to)6468-6477
Number of pages10
JournalClinical Cancer Research
Volume23
Issue number21
DOIs
StatePublished - Nov 1 2017
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Evans, K. W., Yuca, E., Akcakanat, A., Scott, S. M., Arango, N. P., Zheng, X., Chen, K., Tapia, C., Tarco, E., Eterovic, A. K., Black, D. M., Litton, J. K., Yap, T. A., Tripathy, D., Mills, G. B., & Meric-Bernstam, F. (2017). A population of heterogeneous breast cancer patient-derived xenografts demonstrate broad activity of PARP inhibitor in BRCA1/2 wild-type tumors. Clinical Cancer Research, 23(21), 6468-6477. https://doi.org/10.1158/1078-0432.CCR-17-0615