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

摘要

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 na?ve 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 na?ve to treatments; (2) stable‐genome na?ve 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, na?ve 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 na?ve 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.