Schroeder Richard L, Stevens Cheryl L, Sridhar Jayalakshmi
Department of Chemistry, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA.
Ogden College of Science and Engineering, Western Kentucky University, 1906 College Heights Boulevard #11075, Bowling Green, KY 42101, USA.
Molecules. 2014 Sep 23;19(9):15196-212. doi: 10.3390/molecules190915196.
The human epidermal growth factor receptor 2 (HER2) is a member of the erbB class of tyrosine kinase receptors. These proteins are normally expressed at the surface of healthy cells and play critical roles in the signal transduction cascade in a myriad of biochemical pathways responsible for cell growth and differentiation. However, it is widely known that amplification and subsequent overexpression of the HER2 encoding oncogene results in unregulated cell proliferation in an aggressive form of breast cancer known as HER2-positive breast cancer. Existing therapies such as trastuzumab (Herceptin®) and lapatinib (Tyverb/Tykerb®), a monoclonal antibody inhibitor and a dual EGFR/HER2 kinase inhibitor, respectively, are currently used in the treatment of HER2-positive cancers, although issues with high recurrence and acquired resistance still remain. Small molecule tyrosine kinase inhibitors provide attractive therapeutic targets, as they are able to block cell signaling associated with many of the proposed mechanisms for HER2 resistance. In this regard we aim to present a review on the available HER2 tyrosine kinase inhibitors, as well as those currently in development. The use of tyrosine kinase inhibitors as sequential or combinatorial therapeutic strategies with other HER family inhibitors is also discussed.
人表皮生长因子受体2（HER2）是erbB类酪氨酸激酶受体的成员。这些蛋白质通常在健康细胞表面表达，并在负责细胞生长和分化的众多生化途径的信号转导级联反应中发挥关键作用。然而，众所周知，HER2编码癌基因的扩增及随后的过表达会导致一种侵袭性乳腺癌（称为HER2阳性乳腺癌）中细胞的无节制增殖。现有疗法如曲妥珠单抗（赫赛汀®）和拉帕替尼（泰立沙®），分别是一种单克隆抗体抑制剂和一种双靶点EGFR/HER2激酶抑制剂，目前用于治疗HER2阳性癌症，尽管高复发率和获得性耐药问题仍然存在。小分子酪氨酸激酶抑制剂提供了有吸引力的治疗靶点，因为它们能够阻断与许多HER2耐药机制相关的细胞信号传导。在这方面，我们旨在对现有的HER2酪氨酸激酶抑制剂以及目前正在研发的抑制剂进行综述。还讨论了将酪氨酸激酶抑制剂与其他HER家族抑制剂作为序贯或联合治疗策略的应用。
