Cancer is caused by the accumulation of somatic mutations and / or chromosomal rearrangements in key proteins that have a central role in cellular homeostasis. Such proteins participate in a tightly regulated signaling network that in normal cells regulates the balance between cell growth and death. Deregulation of one of these networks, RAS-AKT, is causally involved in cancer initiation and propagation in many different tumor types. Lung cancer is a highly heterogeneous disease and somatic mutations have been documented in approximately 500 known human genes. This high degree of genetic variability is a major cause of innate drug resistance in lung cancer. The RAS and AKT components of the network communicate via interactions at numerous levels that involve positive and negative feedback mechanisms. This facilitates the integration of extracellular signals to efficiently regulate cell growth. Importantly, this network converges at the level of protein translation. Protein translation is an extremely complex process that is primarily controlled at the initiation step, in which many proteins that are activated by extracellular stimuli, assemble on mRNA’s to direct their translation into protein. Protein translation regulation is an active area of research in oncology since it has been determined that deregulation of the initiation step of translation is common in many tumor types, including lung cancer.

The role of AKT - mTOR signaling in the regulation of translation initiation is well  known, however previous studies by we and others have determined a role for RAS signaling in this process, although most of these studies are emerging and not well-defined. We have determined that lung cell lines derived from patients with adenocarcinoma or bronchioloalveolar adenocarcinomas that have mutations in B-RAF (a protein that participates in RAS signaling) have an altered expression profile for a protein that regulates translation initiation. 

Furthermore, lung tumors with mutations in B-RAF have preferential sensitivity to MEK-inhibitors. These MEK-dependent mutations of BRAF in lung cancer occur predominately in women and are independent of smoking status. In addition, K-RAS mutations (a protein that also participates in RAS signaling) are found in 29-22% of in adenocarcinomas and bronchioloalveolar adenocarcinomas and like B-RAF mutations these may demonstrate sensitivity to MEK-inhibitors. Presently, there are two highly specific MEK-inhibitors currently undergoing clinical evaluation, PD0325901 (Pfizer) and AZD6244 (AstraZeneca). Thus, there is great potential for MEK-directed therapy to be utilized in the treatment of lung cancers that have a defined genotype. This enthusiasm is presently moderated by the fact that the molecular determinants of sensitivity to MEK-inhibition have not been sufficiently characterized in either adenocarcinomas, or bronchioloalveolar adenocarcinomas.

Since B-RAF and K-RAS mutations may be preferentially sensitive to MEK-inhibition, the analysis of actively translated RNA species in mutant versus wild-type lung cancer cells after treatment with the MEK-inhibitor PD0325901, may help identify a gene signature that is associated with response to MEK-therapy and potentially may be used to screen relevant patient populations.

A library of B-RAF and  K-RAS mutations that have been characterized and known to occur in lung cancer (specifically adenocarcinomas and bronchioloalveolar adenocarcinomas), will be made and their sensitivity to the MEK inhibitor PD0325901, relative to the wild type proteins will be evaluated. Subsequently, mRNA species that are actively translated into protein will be identified, and the effect of the MEK-inhibitor, PD0325901, on the expression of these specific mRNA species will also be determined. This expression ‘signature’ will be determined for both B-RAF and K-RAS mutant cell types and may predict response to MEK-directed therapy. This work has the potential to identify specific lung cancer genotypes that will benefit from the new class of MEK-directed therapies and as such, offer a highly selective targeted therapy for the approximate one third of lung cancer patients who tumors have somatic mutations in either K-RAS or B-RAF.