Abstract A035: Co-targeting emergent vulnerabilities to overcome FOLFIRINOX resistance in pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy, with a five-year survival rate of just 13%. For the >80% of patients presenting with metastatic disease, standard-of-care systemic chemotherapies such as FOLFIRINOX or gemcitabine/nab-paclitaxel (GnP) inevitably induce resistance, frequently forcing clinicians to switch regimens. Concurrently, chemoresistance is actively supported by a stiff, fibrotic and hypovascular tumour microenvironment. We hypothesise that the selective pressure of surviving chemotherapy within this harsh microenvironment acts as an evolutionary bottleneck, forcing profound adaptation and creating unique, co-targetable acquired vulnerabilities. Leveraging the Australian Pancreatic Cancer Matrix Atlas (APMA) biobank from the Australian Pancreatic Cancer Genome Initiative (APGI), we established an in vivo pipeline mirroring clinical PDAC management. Here, we orthotopically implanted APMA patient-derived xenografts (PDXs) from neoadjuvantly treated patients (FOLFIRINOX or GnP) and re-treated them with continuous or switched chemotherapy regimens. Mass spectrometry proteomics and RNA sequencing revealed that specific treatment sequences drive distinct vulnerabilities. We found that under continuous or switched chemotherapeutic pressure, tumours undergo significant reprogramming to survive the treatment bottleneck. To investigate this further, we will utilise patient-matched, treatment-naïve, and chemotherapy-exposed patient-derived cell lines (PDCLs) to validate new co-targets in vitro. Furthermore, multiphoton intravital imaging via abdominal optical imaging windows will be coupled with biosensors (developed in-house) for AKT and DNA damage biomarkers to enable dynamic, single-cell monitoring of drug response at both primary tumour and metastatic sites (eg. liver). Ultimately, this work aims to elucidate the rewiring that drives chemoresistance and inform the development of novel combination treatments, restoring FOLFIRINOX and broader therapy efficacy for patients with PDAC.