Effect of KRAS Oncogene Substitutions on Protein Behavior:

Approximately 30 % of all human cancers have a mutation in the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), which encodes a GTPase that is essential for normal signaling; mutant KRAS plays a critical role in cancer cell growth and resis-tance to therapy (1). In colorectal cancer, the presence of a KRAS mutation predicts resistance to therapies that target the epidermal growth factor receptor (EGFR) and is predictive of poor prognosis (2). Less clear is the role of KRAS mutations as a predictive factor in non–small cell lung cancer (NSCLC): Some studies have shown a weak association with resistance to treatment and other studies have shown no association (3). KRAS mutations in patient tumors are limited to a few sites; most mutations occur in codon 12, whereas codons 13, 10, and 61 are much less frequently mutated (1). Codon 12 or 13 KRAS mutations result in base changes that lead to amino acid substitu-tions that lock the KRas protein in an active state (4). The frequency and spectrum of KRAS mutations in codons 12 and 13 differs among cancer types. For example, the most common KRA