Novel mechanisms controlling KRAS oncogenic output: impact on tumour fitness and cancer vulnerabilities
The MAPK pathway is a key actor downstream of virtually all known driver oncogenes in lung adenocarcinoma (LUAD). Indeed, using inducible mouse models we have shown that the signal intensity of the MAPK pathway downstream of KRas is a critical factor dictating the nature of the cancer-initiating cell and controlling LUAD progression. Furthermore, accumulating evidences suggest that KRas clusters at the membrane are an essential requirement for the activation of MAPK signalling and to ensure an optimal oncogenic activity. We combine genetic approaches and cellular models to address these two interrelated aspects of KRas biology: the intensity and duration of downstream signalling and the role of KRas clusters at the plasma membrane. I will discuss their biological implications as well as how these observations could identify potential therapeutic approaches to dampen KRas activity.