PO-195 Integrative analysis of in vivo models of pancreatic cancer reveals complex mechanisms behind treatment failure and provides new tools for effective targeting

Introduction Pancreatic cancer remains a highly lethal cancer where response is limited by both intrinsic and acquired chemoresistance. Understanding resistance mechanisms may therefore lead to improved therapeutic strategies. We have recently defined specific molecular subgroups of pancreatic cancer associated with pre-clinical and clinical response to select tailored treatment strategies. 1–3 Material and methods Using robust patient-derived xenografts (PDXs) of pancreatic cancer, here we generated novel in vivo models for the study of intrinsic and acquired chemoresistance mechanisms to clinically-used agents, gemcitabine, mitomycin C, and cisplatin. Here, we used whole genome sequencing (WGS) and microarray analysis to compare gemcitabine-resistant and gemcitabine-sensitive pancreatic tumours to identify relevant resistance mechanisms. Results and discussions Integrative analysis of WGS and microarray profiling of gemcitabine-resistant tumours revealed complex but potentially targetable resistance mechanisms, including increased DNA repair through activation of PARP1, MCM genes and RRM1, and changes within the tumour microenvironment. Importantly, acquired resistance to gemcitabine was effectively reversed by a novel PARP inhibitor, rucaparib, indicating that combination therapy involving this low toxicity agent may be useful in treating gemcitabine-resistant tumours defined by high genomic instability. Similarly, modulation of key components of the tumour microenvironment with fasudil, as recently achieved, 2 provided another effective way of reversing gemcitabine resistance. Conclusion Significance our findings demonstrate the promise of patient-derived xenograft models for the study of in vivo mechanisms of chemotherapy resistance and efficacy testing of novel agents for the treatment of human pancreatic cancer. References Waddell N, et al. Nature (2015) 518(7540):495 Vennin C, et al. Science Translational Medicine (2017) pii: eaai8504 Chou A, et al. Gut (2017) pii: gutjnl-2017-315144 [epub ahead of print]