Her-2/neu(+)
tumor cells refractory to antibody or
receptor tyrosine kinase inhibitors are emerging in treated patients. To investigate if
drug resistant
tumors can be controlled by active vaccination,
gefitinib and antibody sensitivity of four neu(+) BALB/c mouse mammary
tumor lines were compared. Significant differences in cell proliferation and Akt phosphorylation were observed. Treatment-induced drug resistance was associated with increased
chromosomal aberrations as shown by spectral karyotyping analysis, suggesting changes beyond neu signaling pathways. When mice were immunized with pneuTM encoding the extracellular and transmembrane domains of neu, antibody and T-cell responses were induced, and both
drug-sensitive and
drug-resistant
tumor cells were rejected. In T-cell-depleted mice,
drug-sensitive
tumors were still rejected by vaccination, but
drug-refractory
tumors survived in some mice, indicating their resistance to anti-neu
antibodies. To further test if T cells alone can mediate
tumor rejection, mice were immunized with pcytneu encoding full-length cytoplasmic neu that is rapidly degraded by the
proteasome to activate CD8 T cells without inducing antibody response. All test
tumors were rejected in pcytneu-immunized mice, regardless of their sensitivity to
gefitinib or antibody. Therefore, cytotoxic T lymphocytes activated by the complete repertoire of neu
epitopes were effective against all test
tumors. These results warrant Her-2 vaccination whether
tumor cells are sensitive or resistant to Her-2-targeted drugs or antibody
therapy.