Our Pan-RAF inhibitor programme aims to overcome resistance mechanisms associated with clinically approved B-RAF selective drugs
Mutations leading to uncontrolled signalling via the RAS-RAF-MAPK pathway are seen in over one third of all cancers. The RAF kinases (A-RAF, B-RAF and C-RAF) are an integral part of this pathway, with B-RAF mutations commonly seen in the clinic. Although most B-RAFV600E mutant skin cancers are sensitive to approved B-RAF selective drugs, B-RAFV600E mutant colorectal cancers are surprisingly insensitive to these agents due to the functions of other RAF family members. Furthermore, B-RAF selective therapies fail to show clinical benefit against the more prevalent RAS-mutated tumours.
To overcome these resistance mechanisms our scientists are developing a Pan-RAF inhibitor programme. Our lead chemical series has demonstrated in vivo efficacy in a B-RAFV600E mutant colorectal cancer xenograft model, where approved B-RAF selective drugs are ineffective. In addition, this series shows promising activity in RAS-mutated cancer cells.