Non-small cell lung cancer (NSCLC) accounts for approximately 80% of lung cancers. It represents a heterogeneous group of cancers consisting mainly of squamous cell, adeno and large-cell carcinoma. Genetic alterations seen in NSCLC include activation of oncogenes or the inactivation of tumor suppressor genes. Mutations in the K-Ras oncogene inactivate GTPase activity, leading to a continuous transmition of growth signals to the nucleus. K-Ras mutations also affect the PI3K/AKT and Ras/Raf/ERK signaling pathways resulting in uncontrolled cell proliferation and inhibition of apoptosis.Tumor suppressor genes that are inactivated include p53, RASSF1, p16INK4a, FHIT and retinoic acid receptor (RAR)-β. Loss of p16INK4a interferes with the cell cycle while inactivation of p53 results in rapid cellular proliferation and reduced apoptotic signals. RASSF1A forms heterodimers with Nore-1, a RAS effector. Loss of RASSF1A shifts RAS signaling towards growth promoting activity.
Retinoic acid plays an important role in lung development and differentiation, acting primarily via the RAR-β gene. Promoter methylation and silencing of the RAR-β gene is frequently seen in SCLC. Overexpression of c-erbB-2 or EGFR leads to a proliferative advantage via the PI3K/AKT and Ras/Raf/ERK signaling pathways.