Genetic modeling of B - and C- Raf kinase inhibition for the treatment of K-RasG12V driven lung adenocarcinoma

Abstract

Traditionally, cancer patients have been treated with cytotoxic chemotherapies that killed diviging cells by interfering with cell division. This approach has two major drawbacks: (i) due to the lack of selectivity normal dividing cells are also affected resulting in toxicity (ii) patients invariably develop chemoresistant disease. Recently, cancer treatment is moving to so-called ¿targeted therapies¿ rationally designed to interfere with molecules necessary for tumour growth. Targeted cancer therapies are also called precision medicine since they rely on information from tumours for diagnosis and treatment. A number of targeted therapies are currently in the clinic resulting in improved cancer treatment. Infortunately, the development of precision therapies has not yet been possible for certain tumour types that, as a consequence, show poor survival rates. One paradigmatic example is lung adenocarcinomas driven by the K-RAS oncogene. No effective will be abailable until we succeed in identifying good therapeutic targets essential for cancer growth and survival but dispensable for normal cells. To this end we have utilized our inducible K-RasG12V knock-in mouse model to identify essential oncogenic mediators in vivo. With this approach we have previously identified that ablation of ther C-Raf kinase, a component of the MAPK signaling pathway, prevents ther development of K-RasG12V driven lung adenocarcinoma. However, there are essential C-Raf functions with potential cancer implications that are kinase independent. This raises a note of caution regarding ther potential use of C-Raf kinase inhibitors for the treatment of this tumour type. Furthermore, in particular genetic contexts, inhibition of ther closely related B-Raf kinase paradoxically results in hyperactivation of the MAPK pathway, a phenomenon that could be therapeutically counterproductive. The aim of my project was to model, by genetic means, the catalytic inactivation of B- and C-Raf kinases in K-RasG12V driven lung adenocarcinoma and evaluate the potential therapeutic outcome.