2024 New Treatment Grant - Kendelle Murphy

Project Summary

Pancreatic cancer (PC) is a genetically complex, heterogeneous, and treatment-refractory malignancy. PC develops through a multistep process, which is predominantly driven by mutations in the Kras oncogene, present in 90% of patient samples. Kras acts as an on-off switch that, in response to specific signals, becomes activated and stimulates cell growth and division. Mutations in Kras lead to a constitutively activated form of the protein driving uncontrolled cell growth and resistance to cell death signals allowing cancer cells to exhibit immortal proliferation potential. Whilst PC has shown resistance to standard-of-care chemotherapy, new approaches to target mutated Kras show promise in breaking this therapeutic bottleneck. However, pre-clinical investigations have revealed that Kras inhibition leads to enhanced deposition of extracellular matrix (ECM) and fibrosis, which provides positive feedback signalling to tumours, driving resistance and restricting treatment efficacy. We have identified Focal Adhesion Kinase (FAK) – a critical regulator of matrix organisation – as an important contributor to PC progression, regulating ECM density and organisation.