title: DNA vaccination controls Her-2+ tumors that are refractory to targeted therapies.
abstract: 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.
authors.affiliation: Department of Immunology and Microbiology, School of Medicine, Wayne State University, Detroit, Michigan 48201, USA.
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Whittington
authors.forename: Marie P
authors.initials: MP
authors.lastname: Piechocki
authors.forename: Henry H
authors.initials: HH
authors.lastname: Heng
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Jacob
authors.forename: Richard F
authors.initials: RF
authors.lastname: Jones
authors.forename: Jessica B
authors.initials: JB
authors.lastname: Back
authors.forename: Wei-Zen
authors.initials: WZ
authors.lastname: Wei
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D019496:Cancer Vaccines / Q000276:immunology / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D005260:Female; D000077156:Gefitinib; D007621:Karyotyping; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D020032:Tyrphostins; D019444:Vaccines, DNA / Q000276:immunology / Q000494:pharmacology*
chemical_list: D000911:Antibodies, Monoclonal; D019496:Cancer Vaccines; D000077156:Gefitinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020032:Tyrphostins; D019444:Vaccines, DNA; C101044:RTKI cpd
references.citation: Biochemistry. 1990 Dec 18;29(50):11024-8
references.pmid: 1980216
references.citation: Oncogene. 2002 Jan 31;21(6):890-8
references.pmid: 11840334
references.citation: Clin Cancer Res. 2007 Sep 1;13(17):5133-43
references.pmid: 17785568
references.citation: Cancer Res. 2001 Oct 1;61(19):7196-203
references.pmid: 11585755
references.citation: Mol Cell Biol. 1991 Feb;11(2):833-42
references.pmid: 1671296
references.citation: Science. 1989 May 12;244(4905):707-12
references.pmid: 2470152
references.citation: Adv Cancer Res. 2002;85:101-44
references.pmid: 12374283
references.citation: Cancer Res. 2005 Sep 15;65(18):8471-8
references.pmid: 16166327
references.citation: Clin Cancer Res. 2008 Apr 15;14(8):2465-75
references.pmid: 18413839
references.citation: Nature. 1986 Jan 16-22;319(6050):226-30
references.pmid: 3945311
references.citation: Breast Cancer Res Treat. 2008 Dec;112(3):533-43
references.pmid: 18188694
references.citation: Chromosoma. 1993 May;102(5):325-32
references.pmid: 8325164
references.citation: Cancer Res. 2007 Jul 15;67(14):6825-43
references.pmid: 17638894
references.citation: Cancer Res. 2001 Jun 15;61(12):4892-900
references.pmid: 11406568
references.citation: Cancer Res. 2005 Jan 15;65(2):650-6
references.pmid: 15695410
references.citation: J Cell Physiol. 2006 Aug;208(2):461-72
references.pmid: 16688757
references.citation: Science. 1987 Jan 9;235(4785):177-82
references.pmid: 3798106
references.citation: Cancer Lett. 1992 Jul 10;64(3):203-9
references.pmid: 1322235
references.citation: Clin Cancer Res. 2004 Apr 1;10(7):2538-44
references.pmid: 15073134
references.citation: J Leukoc Biol. 1985 Nov;38(5):573-85
references.pmid: 2413152
references.citation: Cancer Res. 2002 Jul 15;62(14):4132-41
references.pmid: 12124352
references.citation: Semin Oncol. 2000 Oct;27(5 Suppl 9):20-6
references.pmid: 11049053
references.citation: Cell Immunol. 2006 Apr;240(2):96-106
references.pmid: 16930573
references.citation: Cancer Treat Rev. 2005 Jun;31(4):312-8
references.pmid: 15979804
references.citation: Genome. 2006 Mar;49(3):195-204
references.pmid: 16604101
references.citation: J Clin Oncol. 2003 Nov 1;21(21):3965-71
references.pmid: 14507946
references.citation: J Immunol Methods. 1983 Dec 16;65(1-2):55-63
references.pmid: 6606682
references.citation: Cancer Res. 2001 Oct 1;61(19):7184-8
references.pmid: 11585753
references.citation: J Clin Oncol. 1998 Feb;16(2):462-9
references.pmid: 9469329
references.citation: Semin Oncol. 1999 Aug;26(4 Suppl 12):51-9
references.pmid: 10482194
references.citation: J Immunol Methods. 2002 Jan 1;259(1-2):33-42
references.pmid: 11730839
references.citation: Cytogenet Cell Genet. 2001;93(3-4):195-202
references.pmid: 11528112
references.citation: Cancer Res. 2001 Dec 15;61(24):8887-95
references.pmid: 11751413
references.citation: Oncogene. 2002 Sep 12;21(41):6255-63
references.pmid: 12214266
references.citation: Cell. 1989 Jun 16;57(6):931-6
references.pmid: 2567634
references.citation: Br J Cancer. 2004 Aug 16;91(4):639-43
references.pmid: 15266327
references.citation: J Immunol. 2001 Sep 15;167(6):3201-6
references.pmid: 11544306
references.citation: EMBO J. 1994 Jul 15;13(14):3302-11
references.pmid: 7913890
references.citation: Int J Cancer. 1999 May 31;81(5):748-54
references.pmid: 10328228
references.citation: J Immunol. 2000 Nov 1;165(9):5133-42
references.pmid: 11046045
references.citation: N Engl J Med. 2005 Oct 20;353(16):1673-84
references.pmid: 16236738
references.citation: Int J Cancer. 2004 Mar 20;109(2):291-301
references.pmid: 14750183
references.citation: J Clin Oncol. 1999 Sep;17(9):2639-48
references.pmid: 10561337
references.citation: Cancer Genet Cytogenet. 2003 Apr 1;142(1):36-45
references.pmid: 12660031
references.citation: EMBO J. 1996 Jan 15;15(2):254-64
references.pmid: 8617201