Acquired Resistance to the Antitumor Effect of Epidermal Growth Factor Receptor-blocking Antibodies in Vivo A Role for Altered Tumor Angiogenesis

摘要: Inhibitors of epidermal growth factor receptor (EGFR) signaling are among the novel drugs showing great promise for cancer treatment in clinic. However, possibility acquired resistance to such because tumor cell genetic instabilities has not yet been explored. Here we report experimental derivation and properties variants obtained from recurrent xenografts human A431 squamous carcinoma, after two consecutive cycles therapy with one three different anti-EGFR monoclonal antibodies: mR3, hR3, or C225. Initial response a 2-week period was generally total regression significantly antibody groups. tumors often reappeared at site inoculation, prolonged latency periods, most became refractory second round therapy. Cell lines established resistant retained high EGFR expression, normal sensitivity ligand, unaltered rate when compared parental line vitro. In contrast, exhibited an accelerated attenuated antibodies vivo relative line. Because reported suppressive effect inhibitors on vascular endothelial (VEGF) demonstrated role VEGF angiogenesis xenografts, expression examined. Five six expressed increased levels VEGF, which paralleled increase both angiogenic potential vitro vivo. addition, elevated cells by gene transfection rendered Taken together, results suggest that, least system, displaying can emerge do so, part, mechanisms involving selection subpopulations potential.