Down-regulation of the erbB-2 receptor by trastuzumab (herceptin) enhancestumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosisin breast and ovarian cancer cell lines that overexpress erbB-2

We investigated whether combined treatment with tumor necrosis factor-relat ed apoptosis-inducing ligand (TRAIL) and trastuzumab could enhance the spec ific killing of cells that overexpress the erbB-2 receptor. The combination resulted in an enhancement of TRAIL-mediated apoptosis in all cell lines o verexpressing erbB-2 receptor compared with either reagent alone. In contra st, there was no effect in cell lines with low levels of the erb-B2 recepto r. Trastuzumab treatment resulted in downregulation of the erbB-2 receptor in all erbs-2-overexpressing cell lines. Similar enhancement of TRAIL toxic ity was observed when the erbB-2 receptor was down-regulated using antisens e oligodeoxynucleotides. Down-regulation of the erbB-2 receptor protein by trastuzumab or antisense oligodeoxynucleotides decreased Akt kinase activat ion but not mitogen-activated protein kinase activation. Down-regulation of Akt kinase activity by a phosphatidylinositol 3 ' -kinase inhibitor (LY294 002) also resulted in enhancement of TRAIL-mediated apoptosis, Expression o f a constitutively active form of Akt kinase in an erbB-2-overexpressing ce ll line completely abrogated the increase in TRAIL-mediated apoptosis by tr astuzumab and significantly reduced the biological effect of either reagent alone. Therefore, down-regulation of the erbB-2 receptor by trastuzumab en hances TRAIL-mediated apoptosis by inhibiting Akt kinase activity. These da ta suggest that the combination of trastuzumab and TRAIL may allow enhanced therapeutic efficacy and specificity in the treatment of erbB-2-overexpres sing tumors.