Molecular mechanisms of lung cancer

Abstract

Lung cancer is a multistep process involving genetic factors and changes in the epigenetic regulation of cell cycle. Gene amplification, overexpression, point mutations or DNA rearrangements may lead to continuous positive regulation of mitogenic growth signals resulting in enhancement of oncogenic cell signaling. This review focuses on disorders of three signaling pathways (RAS-RAF-MEK-ERK, PI3KAkt-mTOR, and Keap1-Nrf2) in lung cancer. The causes for the uncontrolled cell growth and proliferation are EGFR and KRAS mutations and the abnormal EML4-ALK merging, which activate two major pathways of intracellular signaling, RAS-RAF-MEK-ERK and PI3K-AktmTOR. Carcinogenesis in lung cancer may result from genetic aberrations in any component of the PI3K-Akt-mTOR pathway, its negative regulators, interconnected pathways, and the signal transduction through RTK receptors. The disorders of the Keap1-Nrf2 signaling pathway found in lung cancer are caused by somatic mutations, loss of heterozygosity or DNA methylation in the Keap1 promoter region and Nrf2 mutations, which lead to an increase in the accumulation of Nrf2. Tumors with high Nrf2 levels are associated with a poor prognosis due to their radio- and chemoresistance and aggressive proliferation of cancer cells. The Nrf2 hyperactivity helps autonomous malignant cells withstand high levels of endogenous reactive oxygen species (ROS) and evade apoptosis. In this regard, enhancing the Nrf2 activity is an important approach to prevention of cancer while Nrf2 inhibition is desirable for its treatment.