An analysis of pretreatment biopsies from NSCLC patients with EGFR mutations who subsequently received erlotinib reported that the incidence of double EGFR mutations (L88R or exon 9 deletion as well as T79M) was % ( of 9) when using an ultrasensitive assay, with no difference in the initial response to erlotinib (6.6% versus 7.%) in patients with or without T79M mutations, but with a shorter PFS interval in cases in which pretreatment T79M was identified . These findings suggest that the T79M mutation may be present with other EGFR mutations in some patients prior to TKI therapy and may be lected during therapy because of the treatment resistance associated with the mutation. Steric hindrance of TKIs by the “gatekeeper” T79M mutation has been hypothesized as the basis for T79Minduced TKI resistance. However, in vitro, the T79M mutant remains sensitive to irreversible TKIs that are structurally similar to erlotinib and gefitinib, and therefore would be expected to be subject to the same steric hindrance

Yun et all showed that, although the L88R mutation is activating, it also possesses less affinity for ATP than wild-type EGFR. Furthermore, the presence of the T79M mutation increases the ATP affinity of the oncogenic L88R mutant by approximately five-fold. Therefore, enhanced ATP affinity reduces the ability of reversible TKIs such as gefitinib and erlotinib to effectively compete with ATP binding, resulting in a lower potency of reversible TKIs in the setting of the L88R and T79M double mutation . Interestingly, the T79M mutation alone increases the catalytic turnover of EGFR to that of approximately six-fold of the wild-type receptor , indicating that T79M in isolation has oncogenic potential, as reflected by reports of inherited susceptibility to lung cancer and the germline presence of T79M 9, . Less frequent mechanisms of acquired resistance in mutant EGFR NSCLC include amplification of the mesenchymalepithelial transition factor (MET) proto-oncogene  and phosphatidylinositol–kinase (PIK)/Akt activation Bosutinib

MET amplification has been identified in approximately % of mutant EGFR NSCLC tumor specimens that were resistant to erlotinib or gefitinib 6. Sequist et al. 8 recently described other mechanisms of acquired resistance to EGFR inhibitors, including acquisition of PIKCA mutations. In addition, striking examples of histologic transformation to small cell histology and epithelial-to-mesenchymal transition were reported simultaneously, are being investigated to treat NSCLCs that are resistant to first-generation EGFR TKIs . Unlike reversible TKIs, irreversible TKIs contain a reactive Michael-acceptor group that binds covalently with Cys797 present at the ATP-binding cleft of mutant EGFR, thus providing greater presence at the ATP site and overcoming the competition with ATP that becomes unfavorable to reversible purchase Bosutinib

TKIs in the presence of the T79M mutation , 7. The ability of an irreversible TKI to overcome resistance was demonstrated in vitro in mutant EGFR cell lines either clonally selected for resistance by growth in gefitinib or known to harbor the T79M mutation . Several investigational irreversible multitargeted HER family TKIs (Table ) are being evaluated in patients with NSCLC (Table ). These include neratinib or HKI-7 (Wyeth, which was acquired by Pfizer in 9, New London, CT), PF998 (Pfizer), and afatinib or BIBW 99 (Boehringer Ingelheim, Ingelheim, Germany). Neratinib (HKI-7) Neratinib, an irreversible HER family inhibitor that targets EGFR/HER-, HER-, and HER- 8, 9 (Table ), was order Bosutinib evaluated in a phase I trial of patients with advanced solid tumors 6. Neratinib was administered as a single dose followed by a -week observation period  continuous, once-daily treatment with doses in the range of – mg. Grade  diarrhea was observed as a dose-limiting toxicity, and the maximum-tol