Nature. A Braf kinase-inactive mutant induces lung adenocarcinoma

The initiating oncogenic event in almost half of human lung adenocarcinomas is still unknown, a fact that complicates the development of selective targeted therapies. Yet these tumours harbour a number of alterations without obvious oncogenic function including BRAF-inactivating mutations. Researchers at the Spanish National Cancer Research Centre (CNIO) have demonstrated that the expression of an endogenous Braf (D631A) kinase-inactive isoform in mice (corresponding to the human BRAF(D594A) mutation) triggers lung adenocarcinoma in vivo, indicating that BRAF-inactivating mutations are initiating events in lung oncogenesis. The paper, published in Nature, indicates that the signal intensity of the MAPK pathway is a critical determinant not only in tumour development, but also in dictating the nature of the cancer-initiating cell and ultimately the resulting tumour phenotype. 

The RAS–MAPK signalling cascade serves as a central node in transducing signals from membrane receptors to the nucleus. This pathway is aberrantly activated in a substantial fraction of human cancers. There is also abundant evidence that elevated RAS–MAPK signalling results in cellular toxicity that may serve as a natural barrier to cancer progression early in tumorigenesis. These findings suggest that defined thresholds of RAS–MAPK activity are required for homeostasis as well as for malignant transformation, but compelling genetic evidence is missing.

Mutational analysis of different human cancers has recently uncovered that among the BRAF – a component of the RAS-MAP kinase pathway– hot spots in lung adenocarcinoma, those resulting in inactivating mutations predominate over the V600E activating substitution, the main oncogenic form in other tumours such as melanoma. However, the contribution of BRAF-inactive mutants to lung cancer progression is unclear. 

Using public databases, researchers have identified inactivating BRAF mutations in a subset of KRAS-driven human lung tumours. Subsequently, using mouse models, researchers have replicated these observations showing that the co-expression of oncogenic Kras and inactive Braf markedly enhances the onset of lung adenocarcinoma. Also, this combination accelerates tumour progression when the inactivating Braf mutation is genetically induced in advanced tumors. Surprisingly, in this same study it has been shown that, individually, the inactivating mutations of Braf are also oncogenic events that induce the appearance of lung adenocarcinoma.

The paper provides the first genetic evidence demonstrating that a kinase-inactivating Braf mutation induces lung adenocarcinoma development. Moreover, results suggest that lung adenocarcinoma patients with hypoactive BRAF could benefit from therapies based on selective CRAF inhibitors. 

This work has been funded by the European Research Council (ERC-AG/250297-RAS AHEAD), EU Framework Programme (HEALTH-F2-2010-259770/LUNGTARGET and HEALTH-2010-260791/EUROCANPLATFORM), the Spanish Ministry of Economy and Competitiveness (SAF2011-30173 and SAF2014-59864-R), AXA Research Fund, the National Institutes of Health (P01 CA129243; R35 CA210085); the Commonwealth Foundation for Cancer Research, the Center for Experimental Therapeutics at Memorial Sloan Kettering Cancer Center and the Stand Up To Cancer – American Cancer Society Lung Cancer Dream Team Translational Research Grant (SU2C-AACR-DT17-15), the Spanish Ministry of Education and the Spanish Association Against Cancer (AECC).

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