Recapitulating the clinical scenario of BRCA-associated pancreatic cancer in pre-clinical models

Talia Golan*, Chani Stossel, Dikla Atias, Ella Buzhor, Sharon Halperin, Keren Cohen, Maria Raitses-Gurevich, Yulia Glick, Stephen Raskin, Daniel Yehuda, Anna Feldman, Michael Schvimer, Eitan Friedman, Rotem Karni, Julie M. Wilson, Robert E. Denroche, Ilinca Lungu, John M.S. Bartlett, Faridah Mbabaali, Steven GallingerRaanan Berger

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. BRCA-associated PDAC comprises a clinically relevant subtype. A portion of these patients are highly susceptible to DNA damaging therapeutics, however, responses are heterogeneous and clinical resistance evolves. We have developed unique patient-derived xenograft (PDX) models from metastatic lesions of germline BRCA-mutated patients obtained at distinct time points; before treatment and at progression. Thus, closely mimicking clinical scenarios, to further investigate treatment naïve and resistant patients. DNA was isolated from six BRCA-mutated PDXs and classified by whole-genome sequencing to stable-genome or homologous recombination deficient (HRD)-genome. The sensitivity to DNA-damaging agents was evaluated in vivo in three BRCA-associated PDAC PDXs models: (1) HRD-genome naïve to treatments; (2) stable-genome naïve to treatment; (3) HRD-genome resistant to treatment. Correlation between disease course at tissue acquisition and response to PARP inhibitor (PARPi)/platinum was demonstrated in PDXs in vivo. Only the HRD-genome PDX, naïve to treatment, was sensitive to PARP inhibitor/cisplatin treatments. Our results demonstrate heterogeneous responses to DNA damaging agents/PARPi in BRCA-associated PDX thus reflecting the wide clinical spectrum. An HRD-genome PDX generated from a naïve to treatment biopsy was sensitive to platinum/PARPi whereas no benefit was observed in treating a HRD-genome PDXs generated from a patient that had acquired resistance nor stable-genome PDXs.

Original languageAmerican English
Pages (from-to)179-183
Number of pages5
JournalInternational Journal of Cancer
Issue number1
StatePublished - 1 Jul 2018

Bibliographical note

Funding Information:
Key words: pancreatic ductal adenocarcinoma, BRCA, patient-derived xenograft (PDX), PARP inhibitor, treatment na€ıve, treatment resistant Abbreviations: H&E: Hematoxylin and Eosin; HRD: homologous recombination deficient; I.P.: intra-peritoneal; LOH: loss of heterozygosity; NA: not applicable; OS: overall survival; PD: progressive disease; PDAC: pancreatic ductal adenocarcinoma; PDX: patient-derived xenograft; PR: partial response; RECIST: response evaluation criteria in solid tumors; RTV: relative tumor volume; SD: stable disease; SNV: single nucleotide variants; SPF: specific pathogen-free; SV: structural variants; WGS: whole genome sequencing Additional Supporting Information may be found in the online version of this article. *T.G. and C.S. contributed equally to this work Grant sponsor: The Ontario Institute for Cancer Research; Grant sponsor: The Canadian Friends of the Hebrew University (Alex U. Soyka) DOI: 10.1002/ijc.31292 This article was published online on 23 February 2018. An error was subsequently identified. This notice is included in the online and print versions to indicate that both have been corrected 02 March 2018. History: Received 11 Sep 2017; Accepted 23 Jan 2018; Online 3 Feb 2018 Correspondence to: Talia Golan, Medical Director Phase I Program, Oncology Institute, Sheba Medical Center, Tel Hashomer 52621, Israel, Tel.: 972-3-5307099, Fax: 972-3-5352214, E-mail:

Publisher Copyright:
© 2018 UICC


  • BRCA
  • PARP inhibitor
  • pancreatic ductal adenocarcinoma
  • patient-derived xenograft (PDX)
  • treatment naïve
  • treatment resistant


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