title: Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase.
abstract: 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 G(1)-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.
authors.affiliation: Department of Oncology, Wyeth Research, Pearl River, New York, USA. Rabinds@wyeth.com
authors.forename: Sridhar K
authors.initials: SK
authors.lastname: Rabindran
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Discafani
authors.forename: Edward C
authors.initials: EC
authors.lastname: Rosfjord
authors.forename: Michelle
authors.initials: M
authors.lastname: Baxter
authors.forename: M Brawner
authors.initials: MB
authors.lastname: Floyd
authors.forename: Jonathan
authors.initials: J
authors.lastname: Golas
authors.forename: William A
authors.initials: WA
authors.lastname: Hallett
authors.forename: Bernard D
authors.initials: BD
authors.lastname: Johnson
authors.forename: Ramaswamy
authors.initials: R
authors.lastname: Nilakantan
authors.forename: Elsebe
authors.initials: E
authors.lastname: Overbeek
authors.forename: Marvin F
authors.initials: MF
authors.lastname: Reich
authors.forename: Ru
authors.initials: R
authors.lastname: Shen
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Shi
authors.forename: Hwei-Ru
authors.initials: HR
authors.lastname: Tsou
authors.forename: Yu-Fen
authors.initials: YF
authors.lastname: Wang
authors.forename: Allan
authors.initials: A
authors.lastname: Wissner
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D011804:Quinolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D011804:Quinolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C487932:neratinib