Targetable “Driver” Mutations in Non Small Cell Lung Cancer

Abstract

Lung cancer remains the leading cause of cancer-related mortality in the world despite advances in the field of cancer therapeutics. Traditional treatment with empirically chosen cytotoxic chemotherapeutic agents, have given small, but real survival benefits. Recent advances and insights into molecular pathogenesis of lung cancers have provided some novel molecular targets, offering newer strategies and agents that are tumor specific. Studies have identified mutations in specific genes that are involved in driving the development of lung cancer and so it is important to subsequently target them with specific drugs thus changing paradigms of management of this type of cancer. Recently, Lung Cancer Mutation Consortium (LCMC) has identified at least one of the many recognized "driver mutations" in nearly two thirds of the patients with advanced cancer. This study suggests that identification of driver mutations can help in molecular targeted therapeutics and in addition supplant tumor histology in guiding treatment decisions, identifying subset of patients who may benefit therapy. This review focuses on these mutations identified in specific genes serving as "drivers" of lung tumorigenesis and suggests that clear promise for the future of lung cancer treatment is indeed personalized therapy with drugs chosen according to the patient mutation profile. Most clinically relevant translational advances made in genes involved in lung tumorigenesis namely EML4-ALK fusions, HER2, PIK3CA, AKT, BRAF, MAP2K1, MET mutations and amplifications along with the well established EGFR and KRAS mutations are discussed in the context of NSCLCs. These studies emphasize the need for treatment management based on mutation profile along with routine histology based classification of these tumors in future for a directed therapy and thus a better therapeutic outcome.