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  • Original Paper
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Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways


Dual EGFR/erbB2 inhibition is an attractive therapeutic strategy for epithelial tumors, as ligand-induced erbB2/EGFR heterodimerization triggers potent proliferative and survival signals. Here we show that a small molecule, GW572016, potently inhibits both EGFR and erbB2 tyrosine kinases leading to growth arrest and/or apoptosis in EGFR and erbB2-dependent tumor cell lines. GW572016 markedly reduced tyrosine phosphorylation of EGFR and erbB2, and inhibited activation of Erk1/2 and AKT, downstream effectors of proliferation and cell survival, respectively. Complete inhibition of activated AKT in erbB2 overexpressing cells correlated with a 23-fold increase in apoptosis compared with vehicle controls. EGF, often elevated in cancer patients, did not reverse the inhibitory effects of GW572016. These observations were reproduced in vivo, where GW572016 treatment inhibited activation of EGFR, erbB2, Erk1/2 and AKT in human tumor xenografts. Erk1/2 and AKT represent potential biomarkers to assess the clinical activity of GW572016. Inhibition of activated AKT in EGFR or erbB2-dependent tumors by GW572016 may lead to tumor regressions when used as a monotherapy, or may enhance the anti-tumor activity of chemotherapeutics, since constitutive activation of AKT has been linked to chemo-resistance.

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  • Albanell J, Codony-Servat J, Rojo F, Del Campo JM, Sauleda S, Anido J, Raspall G, Giralt J, Rosello J, Nicholson RI, Mendelsohn J, Baselga J . 2001 Cancer Res. 61: 6500–6510

  • Bacus SS, Zelnich CR, Plowman G, Yarden Y . 1994 Am. J. Clin. Path. 102: Suppl S13–S24

  • Brognard J, Clark AS, Dennis PA . 2001 Cancer Res. 61: 3986–3997

  • Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, Wolter J, Paton V, Shak S, Lieberman G, 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, Spalding D . 2001 Bioorganic Med. Chem. Letts. 11: 1401–1405

  • Daly RJ . 1999 Growth Factors 16: 255–263

  • Di Fiore PP, Pierce JH, Fleming TP, Hazan R, Ullrich A, King CR, Schlessinger J, Aaronson SA . 1987 Cell 51: 1063–1070

  • DiMarco E, Pierce JH, Fleming TP, Kraus MH, Molloy CJ, Aaronson SA, DiFiore PP . 1989 Oncogene 4: 831–838

  • Earp HS, Dawson TL, Li X, Yu H . 1995 Breast Cancer Res. Treat. 35: 115–132

  • Egan SE, Weinberg RA . 1993 Nature 365: 781–783

  • Fry DW, Bridges AJ, Denny WA, Doherty A, Greis KD, Hicks JL, Hook KE, Keller PR, Leopold WR, Loo JA, McNamara DJ, Nelson JM, Sherwood V, Smaill JB, Trumpp-Kallmeyer S, Dobrusin EM . 1998 Proc. Natl. Acad. Sci. USA 95: 12022–12027

  • Goldstein NL, Prewett M, Zuklys K, Rockwell P, Mendelsohn J . 1995 Clin. Cancer Res. 1: 1311–1318

  • Grandis JR, Melhem MF, Gooding WE, Day R, Holst VA, Wagener MM, Drenning SD, Tweardy DJ . 1998 J. Natl. Cancer Inst. 90: 824–832

  • Graus-Porta D, Beerli RR, Daly JM, Hynes NE . 1997 EMBO J. 16: 1647–1655

  • Harris RA, Eichholtz TJ, Hiles JD, Page MJ, O'Hare MJ . 1999 Int. J. Cancer 80: 477–484

  • Hoshino R, Chatani Y, Yamori T, Tsuruo T, Oka H, Yoshida O, Shimada Y, Ari-i S, Wada H, Fujimoto J, Kohno M . 1999 Oncogene 18: 813–822

  • Howell GM, Humphrey LE, Awwad RA, Wang D, Koterba A, Periyasamy B, Yang J, Li W, Willson JK, Ziober BL, Coleman K, Carboni J, Lynch M, Brattain MG . 1998 J. Biol. Chem. 273: 9214–9223

  • Hudziak RM, Schlessinger J, Ullrich A . 1987 Proc. Natl. Acad. Sci. USA 84: 7159–7163

  • Janes PW, Daly RJ, deFazio A, Sutherland R . 1994 Oncogene 9: 3601–3608

  • Jiang D, Yang H, Willson JK, Liang J, Humphrey LE, Zborowska E, Wang D, Foster J, Fan R, Brattain MG . 1998 J. Biol. Chem. 273: 31471–31479

  • Karunagaran D, Tzahar E, Beerli RR, Chen X, Graus-Porta D, Ratzkin BJ, Seger R, Hynes NE, Yarden Y . 1996 EMBO J. 15: 254–264

  • Kavanaugh WM, Williams LT . 1994 Science 266: 1862–1865

  • Klapper LN, Kirschbaum MH, Sela M, Yarden Y . 2000 Adv. Cancer Res. 77: 25–79

  • Lane HA, Beuvink I, Motoyama AB, Daly JM, Neve R, Haynes NE . 2000 Mol. Cell. Biol. 20: 3210–3223

  • Levkowitz G, Klapper LN, Tzahar E, Freywald A, Sela M, Yarden Y . 1996 Oncogene 12: 1117–1125

  • Levitzki A, Gazit A . 1995 Science 267: 1782–1787

  • Luttrell DK, Lee TJ, Lansing TJ, Crosby RM, Jung KD, Willard D, Luther M, Rodriguez J, Berman J, Gilmer TM . 1994 Proc. Natl. Acad. Sci. USA 91: 83–87

  • Mendelsohn J . 1997 Clin. Cancer Res. 3: 2703–2707

  • Olayioye MA, Graus-Porta D, Beerli RR, Rohrer J, Gay B, Hynes NE . 1998 Mol. Cell. Biol. 18: 5042–5051

  • Qian XL, Dougall WC, Frei ZZ, Greene MI . 1995 Oncogene 10: 211–219

  • Pulverer BJ, Kyriakis JM, Avruch J, Nikolakaki E, Woodgett JR . 1991 Nature 363: 83–85

  • Reise DJ, Stern DF . 1998 Bioessays 20: 41–48

  • Rusnak DW, Affleck 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, Lackey K . 2001a Cancer Res. 61: 7196–7203

  • Rusnak DW, Lackey K, Affleck K, Wood ER, Alligood KJ, Rhodes N, Keith BR, Murray DM, Glennon K, Knight WB, Mullin RJ, Gilmer TM . 2001b Mol. Cancer Therap. 1: 85–94

  • Salomon DD, Brandt R, Ciardiello F, Normanno N . 1995 Crit. Rev. Oncol. Hematol. 19: 183–232

  • Scott GK, Dodson JM, Montgomery PA, Johnson RM, Sarup JC, Wong WL, Ullrich A, Shepard HM, Benz CC . 1991 J. Biol. Chem. 266: 14300–14305

  • Sibilia M, Wagner EF . 1995 Science 269: 234–238

  • Slamon DJ, Clark SG, Wong WJ, Levin A, Ullrich A, McGuire WL . 1987 Science 235: 177–182

  • Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A, Press MF . 1989 Science 244: 707–712

  • Stern DF, Kamps MP . 1988 EMBO J. 7: 995–1001

  • Tari AM, Lopez-Berestein G . 2000 Int. J. Cancer 86: 295–297

  • Tenzer A, Zingg D, Rocha S, Hemmings B, Fabbro D, Glanzmann C, Schubiger PA, Bodis S, 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, Srivastava RK . 2001 Oncogene 20: 6073–6083

  • Threadgill DW, Dlugosz AA, Hansen LA, Tennenbaum T, Lichti U, Yee D, Lamantia C, Mourton T, Herrup K, Harris RC, Barnard JA, Yuspa SH, Coffey RJ, Magnuson T . 1995 Science 269: 230–234

  • Tzahar E, Waterman H, Chen X, Levkowitz G, Karunagaran D, Lavi S, Ratzkin BJ, Yarden Y . 1996 Mol. Cell. Biol. 16: 5276–5287

  • Ullrich A, Schlessinger J . 1990 Cell 61: 203–212

  • Wada T, Qian XL, Greene MI . 1990 Cell 61: 1339–1347

  • Ye D, Mendelsohn J, Fan Z . 1999 Oncogene 18: 731–738

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The authors would like to thank Tona Gilmer, Karen Lackey, Blaine Knight, Eddie Wood, and Nelson Rhodes for helpful discussions.

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Correspondence to Neil L Spector.

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Xia, W., Mullin, R., Keith, B. et al. Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene 21, 6255–6263 (2002).

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