Abstract
Antibodies and small molecule tyrosine kinase inhibitors targeting ErbB2 exhibit distinct, noncross resistant mechanisms of action. Here, apoptosis of ErbB2-overexpressing breast cancer cells was enhanced by combining lapatinib, an inhibitor of ErbB1 and ErbB2 tyrosine kinases, with anti-ErbB2 antibodies, including (i) trastuzumab, a humanized monoclonal antibody, and (ii) pAb, rabbit polyclonal antisera generated by vaccination with a human ErbB2 fusion protein. Treating ErbB2-overexpressing breast cancer cell lines with a relatively low concentration of lapatinib alone resulted in a minimal increase in tumor cell apoptosis with an associated decrease in steady-state protein levels of p-ErbB2, p-Akt, p-Erk1/2, and notably survivin, compared to baseline. Exposure to pAb alone reduced total ErbB2 protein, disrupting ErbB3 transactivation, leading to a marked inhibition of p-Akt; however, survivin protein levels remained unchanged and apoptosis only increased slightly. Treatment with trastuzumab alone had relatively little effect on survivin and apoptosis was unaffected. Combining lapatinib with either pAb or trastuzumab markedly downregulated survivin protein and enhanced tumor cell apoptosis. The association between the inhibition of survivin and enhanced apoptosis following the combination of ErbB2-targeted therapies provides a biological effect in order to identify therapeutic strategies that promote tumor cell apoptosis and might improve clinical response.
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References
Agus DB, Akita RW, Fox WD, Lewis GD, Higgins B, Pisacane PI, Lofgren JA, Tindell C, Evans DP, Maiese K, Scher HI and Sliwkowski MX . (2002). Cancer Cell, 2, 127–137.
Alimandi M, Romano A, Curia M, Muraro R, Fedi P, Aaronson SA, DiFiore PP and Kraus MH . (1995). Oncogene, 10, 1813–1821.
Arteaga CL . (2003). Exp. Cell Res., 284, 122–130.
Arteaga CL, O'Neil A, Moulder SL, Pins M, Sprano JA, Sledge GW and Davidson NE . (2004). Breast Cancer Res. Treat., 88 (Suppl.), 25a.
Bacus SS, Zelnich CR, Plowman G and Yarden Y . (1994). Am. J. Clin. Path., 102 (Suppl), S13–24.
Baselga J, Norton L, Albanell J, Kim YM and Mendelsohn J . (1998). Cancer Res., 58, 2825–2831.
Brognard J, Clark AS and Dennis PA . (2001). Cancer Res., 61, 3986–3997.
Burris III HA, Storniolo AM, Overmoyer EA, Pegram MD, Jones SF, Peacock NW, Loftiss JI, Koch KM, Beelen PE and Pandite L . (2004). Breast Cancer Res. Treat., 88 (Suppl. 1), 3043a.
Carter BZ, Milella M, Altieri DC and Andreeff M . (2001). Blood, 97, 2784–2790 2001.
Christianson TA, Doherty JK, Lin YJ, Ramsey EE, Holmes R, Keenan EJ and Clinton GM . (1998). Cancer Res., 58, 5123–5129.
Clynes RA, Towers TL, Presta LG and Ravetch JV . (2000). Nat. Med., 6, 443–446.
Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, Wolter J, Paton V, Shak S, Lieberman G and Slamon D . (1999). J. Clin. Oncol., 17, 2639–2648.
Cockerill S, Stubberfield C, Stables J, Carter M, Guntrip S, Smith K, McKeown S, Shaw R, Topley P, Thomsen L, Affleck K, Jowett A, Hayes D, Willson M, Woollard P and Spalding D . (2001). Bioorg. Med. Chem. Lett., 11, 1401–1405.
Du C, Fang M, Li Y, Li L and Wang X . (2000). Cell, 102, 33–42.
Fedi P, Pierce JH, DiFiore PP and Kraus MH . (1994). Mol. Cell Biol., 14, 492–500.
Fry DW . (2003). Exp. Cell Res., 284, 131–139.
Gullick WJ, Love SB, Wright C, Barnes DM, Gusterson B, Harris AL and Altman DG . (1991). Br. J. Cancer, 63, 434–438.
Guy PM, Platko JV, Cantley LC, Cerione RA and Carraway III KL . (1994). Proc. Natl. Acad. Sci. USA, 91, 8132–8136.
Herbst RS, Giaccone G, Schiller JH, Natale RB, Miller V, Manegold C, Scagliotti G, Rosell R, Oliff I, Reeves JA, Wolf MK, Krebs AD, Averbuch SD, Ochs JS, Grous J, Fandi A and Johnson DH . (2004). J. Clin. Oncol., 22, 759–761.
Holbro T, Beerli RR, Maurer F, Koziczak M, Barbas III CF and Hynes NE . (2003). Proc. Natl. Acad. Sci. USA, 100, 8933–8938.
Huang S, Armstrong EA, Benavente S, Chinnaiyan P and Harari PM . (2004). Cancer Res., 64, 5355–5362.
Johnson D . (2002). Ann. Oncol., 13 (Suppl 5), 127.
Li F, Ackermann EJ, Bennett CF, Rothermel AL, Plescia J, Tognin S, Villa A, Marchisio PC and Altieri DC . (1999). Nat. Cell Biol., 1, 461–466.
Maier LA, Xu FJ, Hester S, Boyer CM, McKenzie S, Bruskin MA, Argon Y and Bast JR RC . (1991). Cancer Res., 51, 5361–5369.
Marusawa H, Matsuzawa S-I, Welsh K, Zhou H, Armstrong R, Tamm I and Reed JC . (2003). EMBO J., 22, 2729–2740.
Matar P, Rojo F, Cassia R, Moreno-Bueno G, Di Cosimo S, Tabernero J, Guzman M, Rodriguez S, Arribas J, Palacios J and Baselga J . (2004). Clin. Cancer Res., 10, 6487–6501.
Molina MA, Codony-Servat J, Albanell J, Rojo F, Arribas J and Baselga J . (2001). Cancer Res., 61, 4744–4749.
Molina MA, Saez R, Ramsey EE, Garcia-Barchino M-J, Rojo F, Evans AJ, Albanell J, Keenan EJ, Liuch A, Garcia-Conde J, Baselga J and Clinton GM . (2002). Clin. Cancer Res., 8, 347–353.
Moulder SL, Yakes FM, Muthuswamy SK, Bianco R, Simpson JF and Arteaga CL . (2001). Cancer Res., 61, 8887–8895.
Nagata Y, Lan K-H, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT, Hortobagyi GN, Hung M-C and Yu D . (2004). Cancer Cell, 6, 117–127.
Papapetropoulos A, Fulton D, Mahboubi K, Kalb RG, O'Connor DS, Li F, Altieri DC and Sessa WC . (2000). J. Biol. Chem., 275, 9102–9105.
Park JW, Stagg R, Lewis GD, Carter P, Maneval D, Slamon DJ, Jaffe H and Shepard HM . (1992). Cancer Treatment Res., 61, 193–211.
Pegram M, Hsu S, Lewis G, Pietras R, Beryt M, Sliwkowski M, Coombs D, Baly D, Kabbinavar F and Slamon D . (1999). Oncogene, 18, 2241–2251.
Pietras RJ, Fendly BM, Chazin T, Pegram MD, Howell SB and Slamon DJ . (1994). Oncogene, 9, 1829–1838.
Pinkas-Kramarski R, Soussan L, Waterman J, Levkowitz G, Alroy I, Klapper L, Lavi S, Sager R, Ratzkin BJ, Sela M and Yarden Y . (1996). EMBO J., 15, 2452–2467.
Prigent SA and Gullick WJ . (1994). EMBO J., 13, 2831–2841.
Rodriguez GC, Boente MP, Berchuk A, Whitaker RS, O'Briant KC, Xu F and Bast Jr RC . (1993). Am. J. Obstet. Gynecol., 168, 228–232.
Rusnak DW, Allfleck K, Cockerill SG, Stubberfield C, Harris R, Page M, Smith KJ, Guntrip SB, Carter MC, Shaw RJ, Jowett A, Stables J, Topley P, Wood ER, Brignola PS, Kadwell SH, Reep BR, Mullin RJ, Alligood KJ, Keith BR, Crosby RM, Murray DM, Knight WB, Gilmer TM and Lackey K . (2001). Cancer Res., 61, 7196–7203.
Slamon DJ, Clark SG, Wong WJ, Levin A, Ullrich A and McGuire WL . (1987). Science, 235, 177–182.
Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J and Norton L . (2001). N. Engl. J. Med., 344, 783–792.
Sliwkowski MX, Lofgren J, Lewis GD, Hotaling TE, Fendly BM and Fox JA . (1999). Semin. Oncol., 26 (Suppl 12), 14661–14665.
Song Z, Yao X and Wu M . (2003). J. Biol. Chem., 278, 23130–23140.
Tamm I, Wang Y, Sausville E, Scudiero DA, Vigna N, Oltersdorf T and Reed JC . (1998). Cancer Res., 58, 5315–5320.
Tenzer A, Zingg D, Rocha S, Hemmings B, Fabbro D, Glanzmann C, Schubiger PA, Bodis S and Pruschy M . (2001). Cancer Res., 61, 8203–8210.
Thakkar H, Chen X, Tyan F, Gim S, Robinson H, Lee C, Pandey SK, Nwokorie C, Onwadiwe N and Srivastava RK . (2001). Oncogene, 20, 6073–6083.
Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL, Simpson RJ and Vaux DL . (2000). Cell, 102, 43–53.
Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris JN, Fehrenbacher L, Slamon DJ, Murphy M, Novotny WF, Burchmore M, Shak S, Stewart SJ and Press M . (2002). J. Clin. Oncol., 20, 719–726.
Wood ER, Truesdale AT, McDonald OB, Yuan D, Hassell A, Dickerson SH, Ellis B, Pennisi C, Horne E, Lackey K, Alligood KJ, Rusnak DW, Gilmer TM and Shewchuk L . (2004). Cancer Res., 64, 6652–6659.
Xia W, Mullin RJ, Keith BR, Liu L-H, Ma H, Rusnak DW, Owens G, Alligood KJ and Spector NL . (2002). Oncogene, 21, 6255–6263.
Xia W, Liu L-H, Ho P and Spector NL . (2004). Oncogene, 23, 646–653.
Yarden Y and Sliwkowski MX . (2001). Nat. Rev. Mol. Cell Biol., 2, 127–137.
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Xia, W., Gerard, C., Liu, L. et al. Combining lapatinib (GW572016), a small molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases, with therapeutic anti-ErbB2 antibodies enhances apoptosis of ErbB2-overexpressing breast cancer cells. Oncogene 24, 6213–6221 (2005). https://doi.org/10.1038/sj.onc.1208774
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DOI: https://doi.org/10.1038/sj.onc.1208774
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