KRAS Mutations in Non-Small Cell Lung Cancer

Some non-small cell lung cancers (NSCLCs) harbor a single specific mutated oncogene that is thought to be the primary genetic "driver" leading to cancer. The two most commonly mutated oncogenes in lung cancer encode for the epidermal growth factor receptor (EGFR) and KRAS. EGFR kinase domain mutations were only recently identified, but they have already been established in the clinic as valid predictors of increased sensitivity to EGFR kinase inhibitors (gefitinib and erlotinib). By contrast, even though KRAS mutations were identified in NSCLC tumors more than 20 years ago, we have only just begun to appreciate the clinical value of KRAS tumor status. Recent studies indicate that patients with mutant KRAS tumors fail to benefit from adjuvant chemotherapy, and their disease does not respond to EGFR inhibitors. There is a dire need for therapies specifically for patients with KRAS mutant NSCLC. In this review, we summarize the initial discovery of RAS mutations in NSCLC, describe work exploring associations with clinical factors and outcomes, and provide an overview of current approaches to targeting KRAS mutant NSCLC.