Novel insights into KRas biology identify potential therapeutic strategies
Institut Européen de Chimie et Biologie [Pessac / Bordeaux, France]
We have utilized a genetic approach to address two interrelated aspects of KRas biology: the intensity and duration of downstream signalling and the role of KRas dimerization at the plasma membrane. We have paid special attention to the MAPK pathway due to its fundamental implication downstream of virtually all known driver oncogenes in lung adenocarcinoma (LUAD). Data from inducible mouse models indicate that the signal intensity of the MAPK pathway is a critical determinant not only in LUAD development, but also in dictating the nature of the cancer-initiating cell and ultimately the resulting tumour phenotype (1). Furthermore, we have recently identified KRas dimerization (2) as an essential requirement for the activation and possibly regulation of MAPK signalling intensity in vivo and ultimately for its oncogenic activity.
1.- Nieto P, Ambrogio C, De Esteban L, Gómez-López G, Blasco T, Yao Z, Marais R, Rosen N, Chiarle R, Pisano DG, Barbacid M and Santamaría D. (2017) A B-Raf kinase inactive mutant induces lung adenocarcinoma. Nature 548, 239-43.
2.- Ambrogio C, Köhler J, Zhou Z, Wang H, Paranal R, Li J, Capelletti M, Caffarra C, Li S, Gondi S, Hunter JC, Chiarle R, Santamaría D, Westover K.D. and Jänne P.A. (2018) KRAS dimerization impairs sensitivity to MEK inhibitors and is essential for oncogenic activity of mutant KRAS. Cell 172(4), 857-68.e15.