subject: In Inhibiting The Survival Of Human [print this page] which can be blocked by the HDAC inhibitor MS-275.44 Notably, treating gefitinib- resistant NSCLC cells with MS-275 increased E-cadherin and EGFR expression and restored sensitivity to EGFR TKIs.44 E-cadherin expression was determined in a small subset of patients (87 [8%] of 1079) who participated in the TRIBUTE trial.43 In patients whose tumors expressed E-cadherin, median TTP was longer with erlotinib plus MG-132 carboplatin/paclitaxel than with carboplatin/ paclitaxel alone (34.0 vs 19.3 weeks; HR, 0.37; P = 0.003).43 Conversely, median TTP did not differ significantly between treatment regimens in the E-cadherin-negative subgroup.43 Additional analyses in larger cohorts will be needed to validate
E-cadherin as a marker of resistance to EGFR TKIs in patients with advanced NSCLC. In summary, there are multiple strategies that may be used to develop new agents that may overcome or delay the emergence of acquired resistance to first-generation EGFR TKIs. Specifically, there is a need for agents that reduce signaling through pathways downstream of EGFR (e.g., KRAS), pathways that overlap or signal in parallel with EGFR (e.g., MET, VEGFR, and IGF-1R), and through those that promote EMT. It should be noted that although this review focuses on resistance to EGFR TKIs, treatment strategies with EGFR-targeted monoclonal antibodies may have to overcome similar mechanisms of resistance (e.g., KRAS mutation). Next-generation EGFR TKIs include irreversible MG-132 133407-82-6 inhibitors that simultaneously target multiple members of the EGFR family (Table 1). The first-generation agents, gefitinib and erlotinib, bind to the catalytic site of the EGFR TK domain through competitive binding with ATP.18 The irreversible binding mechanism of nextgeneration TKIs and resulting reduced off-rate may increase TKI effectiveness by prolonging the inhibition of EGFR signaling and reducing the emergence of resistance.
An irreversible EGFR TKI may overcome resistance to gefitinib or erlotinib through covalently binding to EGFR and, once bound, will no longer be in a competitive, reversible equilibrium with ATP.45 In 1 study, 49 NCIH1650 bronchioloalveolar cell clones showed decreased sensitivity to gefitinib, but clones resistant to an irreversible inhibitor could not be established.46 In addition, irreversible inhibitors reduced proliferation in cells with an EGFR-activating mutation as well as in those with a secondary, resistance-associated EGFR mutation.46 Two irreversible inhibitors of multiple EGFR family members are buy MG-132 currently being evaluated for the treatment of NSCLC in phase III clinical trials: afatinib (BIBW 2992) (Boehringer Ingelheim; Ingelheim, Germany), an EGFR/HER2 inhibitor, and PF-00299804 (Pfizer; New London, CT, US), an agent with activity against EGFR, HER2, and HER4.47,48 Other irreversible and/or multitargeted TKIs, including lapatinib (GlaxoSmithKline; London, UK) and neratinib (Pfizer; New London, CT, US), have also been evaluated in NSCLC.
Results from preclinical studies indicate that afatinib inhibits the kinase activity of wild-type and mutant forms of EGFR and HER2.47 In cell-free assays, afatinib has a potency similar to that of gefitinib for inhibiting L858R EGFR (IC50 of 0.4 nM vs 0.8 nM) and comparable to lapatinib for inhibiting HER2 (IC50 of 14 nM vs 15 nM). However, afatinib has shown 100-fold greater activity against L858R/T790M EGFR double mutants than gefitinib (IC50, 10 nM vs 1013 nM).47 Moreover, afatinib was more effective than erlotinib, gefitinib, and lapatinib in inhibiting the survival of human NSCLC cell lines harboring wild-type EGFR or the L858R/ T790M double mutant.47 In a xenograft model of the epidermoid carcinoma cell line A431, which expresses high levels of EGFR and detectable HER2 levels, afatinib was more effective in suppressing tumor growth than maximally tolerated doses of gefitinib or lapatinib.47 Afatinib also showed activity in tumor xenograft models resistant to first-generation EGFR TKIs, including tumors har
