Early glandular neoplasia of the lung

Although bronchogenic carcinomas progress through a very well defined sequence of metaplasia, dysplasia and carcinoma in situ, very little is known about the early progression of glandular neoplasms of the lung. In particular, the early precursor lesion from which fully malignant adenocarcinomas arise has effectively eluded recognition, at least until recently. Several lines of evidence now implicate atypical adenomatous hyperplasia (AAH) as an initial morphologic stage in multistep lung tumorigenesis. Despite its small size, AAH can be appreciated at the light microscopic level and characterized at the molecular genetic level. Indeed, the genetic characterization of AAH promises to further our understanding of lung cancer development and might facilitate the design of novel strategies for early detection of lung cancer

K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions

Somatic mutations in the small GTPase K-Ras are the most common activating lesions found in human cancer, and are generally associated with poor response to standard therapies(1–3). Efforts to target this oncogene directly have faced difficulties owing to its picomolar affinity for GTP/GDP(4) and the absence of known allosteric regulatory sites. Oncogenic mutations result in functional activation of Ras family proteins by impairing GTP hydrolysis(5,6). With diminished regulation by GTPase activity, the nucleotide state of Ras becomes more dependent on relative nucleotide affinity and concentration. This gives GTP an advantage over GDP(7) and increases the proportion of active GTP-bound Ras. Here we report the development of small molecules that irreversibly bind to a common oncogenic mutant, K-Ras(G12C). These compounds rely on the mutant cysteine for binding and therefore do not affect the wild-type protein. Crystallographic studies reveal the formation of a new pocket that is not apparent in previous structures of Ras, beneath the effector binding switch-II region. Binding of these inhibitors to K-Ras(G12C) disrupts both switch-I and switch-II, subverting the native nucleotide preference to favour GDP over GTP and impairing binding to Raf. Our data provide structure-based validation of a new allosteric regulatory site on Ras that is targetable in a mutant-specific manner