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

Area of Science:

• Oncology
• Genetics
• Cancer Biology

Background:

• Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer.
• BRCA-mutated PDAC is a subtype with potential therapeutic vulnerabilities.
• Treatment responses in BRCA-associated PDAC are variable, and clinical resistance is a significant challenge.

Purpose of the Study:

• To develop and utilize patient-derived xenograft (PDX) models of BRCA-mutated PDAC.
• To investigate the differential sensitivity of treatment-naïve versus treatment-resistant BRCA-mutated PDAC to DNA damaging agents.
• To correlate genomic status (stable vs. homologous recombination deficient - HRD) with treatment response.

Main Methods:

• Generation of PDX models from metastatic lesions of germline BRCA-mutated PDAC patients at pre-treatment and progression time points.
• Whole-genome sequencing to classify PDX genomes as stable or HRD.
• In vivo evaluation of sensitivity to DNA-damaging agents, including PARP inhibitors (PARPi) and platinum compounds, in distinct PDX models.

Main Results:

• Only the HRD-genome PDX model, derived from a treatment-naïve biopsy, demonstrated sensitivity to PARP inhibitor and cisplatin treatments.
• HRD-genome PDX models derived from patients with acquired resistance showed no benefit from PARPi/platinum.
• Stable-genome PDX models did not respond to the tested DNA damaging agents.

Conclusions:

• BRCA-associated PDAC exhibits heterogeneous responses to DNA damaging agents and PARP inhibitors, mirroring the clinical spectrum.
• Genomic status (HRD) and treatment history (naïve vs. resistant) are critical determinants of therapeutic sensitivity in BRCA-mutated PDAC.
• HRD-genome PDX models are valuable tools for studying treatment resistance mechanisms and evaluating therapeutic strategies in PDAC.