This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rabindran, S. K. Articles by Wissner, A. Search for Related Content PubMed PubMed Citation Articles by Rabindran, S. K. Articles by Wissner, A.

Antitumor Activity of HKI-272, an Orally Active, Irreversible Inhibitor of the HER-2 Tyrosine Kinase

Departments of ¹ Oncology and ² Chemical & Screening Sciences, Wyeth Research, Pearl River, New York

HER-2 belongs to the ErbB family of receptor tyrosine kinases, which has been implicated in a variety of cancers. Overexpression of HER-2 is seen in 25–30% of breast cancer patients and predicts a poor outcome in patients with primary disease. Trastuzumab (Herceptin), a monoclonal antibody to HER-2, is specifically approved for HER-2-positive breast cancer but is active only in a subset of these tumors. Blocking HER-2 function by a small molecule kinase inhibitor, therefore, represents an attractive alternate strategy to inhibit the growth of HER-2-positive tumors. HKI-272 is a potent inhibitor of HER-2 and is highly active against HER-2-overexpressing human breast cancer cell lines in vitro. It also inhibits the epidermal growth factor receptor (EGFR) kinase and the proliferation of EGFR-dependent cells. HKI-272 reduces HER-2 receptor autophosphorylation in cells at doses consistent with inhibition of cell proliferation and functions as an irreversible binding inhibitor, most likely by targeting a cysteine residue in the ATP-binding pocket of the receptor. In agreement with the predicted effects of HER-2 inactivation, HKI-272 treatment of cells results in inhibition of downstream signal transduction events and cell cycle regulatory pathways. This leads to arrest at the G₁-S (Gap 1/DNA synthesis)-phase transition of the cell division cycle, ultimately resulting in decreased cell proliferation. In vivo, HKI-272 is active in HER-2- and EGFR-dependent tumor xenograft models when dosed orally on a once daily schedule. On the basis of its favorable preclinical pharmacological profile, HKI-272 has been selected as a candidate for additional development as an antitumor agent in breast and other HER-2-dependent cancers.

This article has been cited by other articles:

				K.-K. Wong, P. M. Fracasso, R. M. Bukowski, T. J. Lynch, P. N. Munster, G. I. Shapiro, P. A. Janne, J. P. Eder, M. J. Naughton, M. J. Ellis, et al. A Phase I Study with Neratinib (HKI-272), an Irreversible Pan ErbB Receptor Tyrosine Kinase Inhibitor, in Patients with Solid Tumors Clin. Cancer Res., April 1, 2009; 15(7): 2552 - 2558. [Abstract] [Full Text] [PDF]

				A. J. Gonzales, K. E. Hook, I. W. Althaus, P. A. Ellis, E. Trachet, A. M. Delaney, P. J. Harvey, T. A. Ellis, D. M. Amato, J. M. Nelson, et al. Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor Mol. Cancer Ther., July 1, 2008; 7(7): 1880 - 1889. [Abstract] [Full Text] [PDF]

				N. Godin-Heymann, L. Ulkus, B. W. Brannigan, U. McDermott, J. Lamb, S. Maheswaran, J. Settleman, and D. A. Haber The T790M "gatekeeper" mutation in EGFR mediates resistance to low concentrations of an irreversible EGFR inhibitor Mol. Cancer Ther., April 1, 2008; 7(4): 874 - 879. [Abstract] [Full Text] [PDF]

				H.-P. Kim, S.-W. Han, S.-H. Kim, S.-A. Im, D.-Y. Oh, Y.-J. Bang, and T.-Y. Kim Combined lapatinib and cetuximab enhance cytotoxicity against gefitinib-resistant lung cancer cells Mol. Cancer Ther., March 1, 2008; 7(3): 607 - 615. [Abstract] [Full Text] [PDF]

				S. V. Sharma and J. Settleman Oncogene addiction: setting the stage for molecularly targeted cancer therapy Genes & Dev., December 15, 2007; 21(24): 3214 - 3231. [Abstract] [Full Text] [PDF]

				Z. Yu, T. J. Boggon, S. Kobayashi, C. Jin, P. C. Ma, A. Dowlati, J. A. Kern, D. G. Tenen, and B. Halmos Resistance to an Irreversible Epidermal Growth Factor Receptor (EGFR) Inhibitor in EGFR-Mutant Lung Cancer Reveals Novel Treatment Strategies Cancer Res., November 1, 2007; 67(21): 10417 - 10427. [Abstract] [Full Text] [PDF]

				L. Toral-Barza, W.-G. Zhang, X. Huang, L. A. McDonald, E. J. Salaski, L. R. Barbieri, W.-D. Ding, G. Krishnamurthy, Y. B. Hu, J. Lucas, et al. Discovery of lactoquinomycin and related pyranonaphthoquinones as potent and allosteric inhibitors of AKT/PKB: mechanistic involvement of AKT catalytic activation loop cysteines Mol. Cancer Ther., November 1, 2007; 6(11): 3028 - 3038. [Abstract] [Full Text] [PDF]

				K.-K. Wong HKI-272 in Non Small Cell Lung Cancer Clin. Cancer Res., August 1, 2007; 13(15): 4593s - 4596s. [Abstract] [Full Text] [PDF]

				L. V. Sequist Second-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer Oncologist, March 1, 2007; 12(3): 325 - 330. [Abstract] [Full Text] [PDF]

				M. Perez-Torres, M. Guix, A. Gonzalez, and C. L. Arteaga Epidermal Growth Factor Receptor (EGFR) Antibody Down-regulates Mutant Receptors and Inhibits Tumors Expressing EGFR Mutations J. Biol. Chem., December 29, 2006; 281(52): 40183 - 40192. [Abstract] [Full Text] [PDF]

				T. W. Wong, F. Y. Lee, C. Yu, F. R. Luo, S. Oppenheimer, H. Zhang, R. A. Smykla, H. Mastalerz, B. E. Fink, J. T. Hunt, et al. Preclinical Antitumor Activity of BMS-599626, a pan-HER Kinase Inhibitor That Inhibits HER1/HER2 Homodimer and Heterodimer Signaling. Clin. Cancer Res., October 15, 2006; 12(20): 6186 - 6193. [Abstract] [Full Text] [PDF]

				J. V. Heymach, M. Nilsson, G. Blumenschein, V. Papadimitrakopoulou, and R. Herbst Epidermal growth factor receptor inhibitors in development for the treatment of non-small cell lung cancer. Clin. Cancer Res., July 15, 2006; 12(14): 4441s - 4445s. [Abstract] [Full Text] [PDF]

				T. Shimamura, H. Ji, Y. Minami, R. K. Thomas, A. M. Lowell, K. Shah, H. Greulich, K. A. Glatt, M. Meyerson, G. I. Shapiro, et al. Non-Small-Cell Lung Cancer and Ba/F3 Transformed Cells Harboring the ERBB2 G776insV_G/C Mutation Are Sensitive to the Dual-Specific Epidermal Growth Factor Receptor and ERBB2 Inhibitor HKI-272. Cancer Res., July 1, 2006; 66(13): 6487 - 6491. [Abstract] [Full Text] [PDF]

				J. Baselga Is There a Role for the Irreversible Epidermal Growth Factor Receptor Inhibitor EKB-569 in the Treatment of Cancer? A Mutation-Driven Question J. Clin. Oncol., May 20, 2006; 24(15): 2225 - 2226. [Full Text] [PDF]

				H. Ji, X. Zhao, Y. Yuza, T. Shimamura, D. Li, A. Protopopov, B. L. Jung, K. McNamara, H. Xia, K. A. Glatt, et al. Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors PNAS, May 16, 2006; 103(20): 7817 - 7822. [Abstract] [Full Text] [PDF]

				C. V. Lund, M. Popkov, L. Magnenat, and C. F. Barbas III Zinc Finger Transcription Factors Designed for Bispecific Coregulation of ErbB2 and ErbB3 Receptors: Insights into ErbB Receptor Biology Mol. Cell. Biol., October 15, 2005; 25(20): 9082 - 9091. [Abstract] [Full Text] [PDF]

				T. A. Carter, L. M. Wodicka, N. P. Shah, A. M. Velasco, M. A. Fabian, D. K. Treiber, Z. V. Milanov, C. E. Atteridge, W. H. Biggs III, P. T. Edeen, et al. Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases PNAS, August 2, 2005; 102(31): 11011 - 11016. [Abstract] [Full Text] [PDF]

				E. L. Kwak, R. Sordella, D. W. Bell, N. Godin-Heymann, R. A. Okimoto, B. W. Brannigan, P. L. Harris, D. R. Driscoll, P. Fidias, T. J. Lynch, et al. Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib PNAS, May 24, 2005; 102(21): 7665 - 7670. [Abstract] [Full Text] [PDF]

				D.A. HABER, D.W. BELL, R. SORDELLA, E.L. KWAK, N. GODIN-HEYMANN, S.V. SHARMA, T.J. LYNCH, and J. SETTLEMAN Molecular Targeted Therapy of Lung Cancer: EGFR Mutations and Response to EGFR Inhibitors Cold Spring Harb Symp Quant Biol, January 1, 2005; 70(0): 419 - 426. [Abstract] [PDF]