The L858R substitution is the single most common mutation (approximately 40% of all muta tions), and it lies in the activation loop (A loop) of the kinase. Point mutations are also observed in glycine719, although less frequently. Gly719 is found in the adjacent phosphate-binding ‘‘P loop’’ of the kinase and is substituted with serine, cysteine, or alanine. The L858R and G719S point mutations, as well as the exon 19 dele- tions and exon 20 insertions, are transforming when intro- duced into a variety of cell lines, including fibroblasts and lung epithelial cells (Lynch et al., 2004; Sordella et al.,2004; Arao et al., 2004; Greulich et al., 2005; Amann et al., 2005; Engelman et al., 2005).