Abstract

Tumour cells with mutations in BRAF or KRAS exhibit de-regulated activation of the MEK1/2-ERK1/2 signalling pathway, which drives their malignant properties. Such tumour cells typically exhibit an addiction to ERK1/2 signalling and this has fuelled the development of therapies that target specific components of the pathway. BRAFi and MEKi are approved in the clinic whilst multiple ERKi are in development.
Whilst BRAFi and MEKi significantly improve survival in BRAF-mutant melanoma, responses are often short-lived, due to the emergence of tumour cells with acquired resistance; this typically arises by maintaining or reactivating the ERK1/2 pathway in the presence of drug. Responses to MEKi in KRAS-mutant tumours are further limited by a variety of innate resistance mechanisms. Understanding the molecular changes that drive resistance allows us to identify novel tumour cell vulnerabilities. These may provide rational strategies to improve primary efficacy and to overcome acquire resistance.