The combination of a TKI and a mAb was explored as a potential strategy to overcome acquired resistance to first generation EGFR TKIs. Kim and colleagues demonstrated that the combination of lapatinib with cetuximab over came gefitinib resistance due to the secondary T790M mutation in NSCLC by inducing enhanced cytotoxicity both in vitro and in vivo. Furthermore, former the association of cetuximab with afatinib has been shown to be effective to overcome T790M mediated drug resistance. However, the combination of erlotinib with cetuxi mab did not lead to a significant radiological response in NSCLC patients with clinically defined acquired resistance to erlotinib indicating that such strategy is not sufficient to overcome acquired resistance to Inhibitors,Modulators,Libraries erlo tinib.
The mechanisms leading to an enhanced activity of combining Inhibitors,Modulators,Libraries a TKI with a monoclonal antibody have been ascribed, in other cancer cell models, either to a more efficient inhibition of TK receptors or to an increased targeted receptors Inhibitors,Modulators,Libraries on plasma membrane induced by TKIs. Scaltriti et al. showed that lapatinib enhanced the effects of trastuzumab by in ducing HER 2 stabilization and accumulation at the cell surface of breast cancer cell lines, and Mimura et al. reported that lapatinib induced accumu lation of HER 2 and EGFR on esophageal cancer cell lines evoking trastuzumab and cetuximab mediated ADCC. ADCC, one of the killing mechanism of the immune system mediated by Natural Killer cells, plays a pivotal role in the anti cancer effects exerted by mAbs. There fore, increasing the ADCC activity is an important objective in the development of novel therapeutic approaches.
It has been recently demonstrated that the EGFR inhi bitors gefitinib and erlotinib enhance the susceptibility to NK cell mediated lysis of A549, NCI H23 and SW 900 lung cancer cell lines by the induction of ULBP1. Inhibitors,Modulators,Libraries These data indicate Inhibitors,Modulators,Libraries that EGFR blockade could not be the only mechanism of action of EGFR inhibitors in vivo. The efficacy of these inhibitors in lung cancer www.selleckchem.com/products/brefeldin-a.html may be at least in part mediated by increased suscepti bility to NK activity. Moreover, cetuximab serves as a potent stimulus for NK functions including INF gamma production and is also associated with a comple ment mediated immune response. We here demonstrated that erlotinib induces an accu mulation of EGFR and/or HER2 protein at the plasma membrane level only in TKI sensitive NSCLC cell lines whereas, in resistant cells, this en hancement was not observed. The anti tumour effect of drug combination was more evident in ADCC experi ments compared with cell viability experiments.