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

Abstract

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 an HRD-genome PDXs generated from a patient that had acquired resistance nor stable-genome PDXs. This article is protected by copyright. All rights reserved.

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