RESUMO
Lung adenocarcinoma is comprised of distinct mutational subtypes characterized by mutually exclusive oncogenic mutations in RTK/RAS pathway members KRAS, EGFR, BRAF and ERBB2, and translocations involving ALK, RET and ROS1. Identification of these oncogenic events has transformed the treatment of lung adenocarcinoma via application of therapies targeted toward specific genetic lesions in stratified patient populations. However, such mutations have been reported in only â¼55% of lung adenocarcinoma cases in the United States, suggesting other mechanisms of malignancy are involved in the remaining cases. Here we report somatic mutations in the small GTPase gene RIT1 in â¼2% of lung adenocarcinoma cases that cluster in a hotspot near the switch II domain of the protein. RIT1 switch II domain mutations are mutually exclusive with all other known lung adenocarcinoma driver mutations. Ectopic expression of mutated RIT1 induces cellular transformation in vitro and in vivo, which can be reversed by combined PI3K and MEK inhibition. These data identify RIT1 as a driver oncogene in a specific subset of lung adenocarcinomas and suggest PI3K and MEK inhibition as a potential therapeutic strategy in RIT1-mutated tumors.
Assuntos
Adenocarcinoma/genética , Neoplasias Pulmonares/genética , Proteínas ras/genética , Proteínas ras/metabolismo , Adenocarcinoma/patologia , Animais , Antineoplásicos/farmacologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Humanos , Neoplasias Pulmonares/patologia , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Nus , Mutação , Células NIH 3T3 , Neoplasias Experimentais , Células PC12 , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Ratos , Estados Unidos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We propose an abstraction method for medium-scale biomolecular networks, based on hybrid dynamical systems with continuous multi-affine dynamics. This abstraction method follows naturally from the notion of approximating nonlinear rate laws with continuous piecewise linear functions and can be easily automated. An efficient reachability algorithm is possible for the resulting class of hybrid systems. An efficient reachability algorithm is possible for the resulting class of hybrid systems. An approximation for an ordinary differential equation model of the lac operon is constructed, and it is shown that the abstraction passes the same experimental tests as were used to validate the original model. The well studied biological system exhibits bistability and switching behaviour, arising from positive feedback in the expression mechanism of the lac operon. The switching property of the lac system is an example of the major qualitative features that are the building blocks of higher level, more coarse-grained descriptions. The present approach is useful in helping to correctly identify such properties and in connecting them to the underlying molecular dynamical details. Reachability analysis together with the knowledge of the steady-state structure are used to identify ranges of parameter values for which the system maintains the bistable switching property.
