Mutations in the KRAS oncogene play a critical role in cancer cell growth and resistance to treatment. In colorectal cancer, the presence of any mutant amino acid substitution in the K-Ras protein predicts a poorer response to targeted therapy. In non–small cell lung cancer (NSCLC), however, there is conflicting evidence on whether KRAS mutations are predictive of poorer outcome.
Ihle and colleagues from The University of Texas MD Anderson Cancer Center in Houston recently assessed associations between specific mutant K-Ras proteins and progression-free survival and tumor gene expression in NSCLC tissue from 215 patients involved in a clinical trial of molecular targeted therapy.1 Patients who had tumors with either K-Ras Gly12Cys or Gly12Val substitutions had significantly worse progression-free survival (median, 1.84 months) than did patients with other mutant K-Ras proteins (median, 3.35 months) or wild-type K-Ras proteins (median, 1.95 months). Evaluation of signaling pathway activation in a panel of 67 NSCLC cell lines showed that those with the Gly12Cys or Gly12Val mutations had activated Ral signaling and decreased growth factor–dependent Akt activation, whereas those with the Gly12Asp substitution exhibited activated PI3K and MEK (MAPK/ERK kinase).
Molecular modeling studies indicated that different conformations resulting from different K-Ras mutants may result in different associations with downstream signaling transducers. As stated by the investigators, “Not all mutant K-Ras proteins affect patient survival or downstream signaling in a similar way. The heterogeneous behavior of mutant K-Ras proteins implies that therapeutic interventions may need to take into account the specific mutant K-Ras expressed by the tumor.” ■
1. Ihle NT, Byers LA, Kim ES, et al: Effect of KRAS oncogene substitutions on protein behavior: Implications for signaling and clinical outcome. J Natl Cancer Inst 104:228-239, 2012.