KRAS mutations are prevalent in pancreatobiliary tumours, allowing uncontrolled activation of downstream signalling through the MEK/ERK and PI3K pathways. These pathways are therefore an attractive therapeutic target; however, complex cross-talk and feedback mechanisms make inhibition challenging.
To better understand this complexity, we have treated the clinically relevant KPC pancreatic cancer mouse model with combinations of inhibitors of pathways downstream of KRAS signalling. Strikingly, with one such combinatorial strategy targeting these pathways, we saw not only significant survival extension in tumour-bearing mice, but also rapid tumour regressions. Analysis of downstream targets revealed decreases in signalling through the targeted pathways, along with a significant decrease in proliferation and an increase in apoptotic cell death. Mice did relapse, however, and although target inhibition was maintained in tumour cells, some activation of downstream targets was observed in stromal cells, accompanied by a significant increase in fibrosis and extracellular matrix deposition. These data suggest that stromal cells respond differently to tumour cells in the context of pathway inhibition, and that they may promote relapse or resistance following targeted inhibition.
We also recently generated an autochthonous model of cholangiocarcinoma that recapitulates the human disease at both the histological and transcriptomic levels. Interestingly, targeted inhibition of the same KRAS-driven signalling pathways was also effective in this model, however, upon relapse, inhibition of key effectors was maintained in the stroma but not in the tumour cells, indicating a completely distinct resistance mechanism.
Collectively, our data demonstrate the importance of these signalling pathways in pancreatobiliary cancers, playing a crucial role in tumour progression and treatment resistance, and suggesting future therapeutic strategies for these aggressive malignancies.