Albanell Joan, Codony Jordi, Rovira Ana, Mellado Begoña, Gascón Pere
ICMHO, Laboratory of Oncology Research, Medical Oncology Service, Hospital Clinic i Provincial de Barcelona, Spain.
Adv Exp Med Biol. 2003;532:253-68. doi: 10.1007/978-1-4615-0081-0_21.
The HER family of transmembrane tyrosine kinase receptors is composed of four members, BER1 to HER4. HER2 is a ligand-orphan receptor expressed in many human tumors and overexpressed in 25-30% of breast cancers. HER2 amplifies the signal provided by other receptors of the HER family by forming heterodimers. The essential role of HER2 in the HER signaling network led to the development of anti-HER2 monoclonal antibodies (MAbs) for cancer therapy. In particular, the humanized MAb trastuzumab (Herceptin) has antitumor activity against HER2-overexpressing human breast tumor cells and is widely used for the treatment of women with HER2 overexpressing breast cancers. Trastuzumab induces HER2 receptor downmodulation and, as a result, inhibits critical signalling pathways (i.e. ras-Raf-MAPK and PI3K/Akt) and blocks cell cycle progression by inducing the formation of p27/Cdk2 complexes. Trastuzumab also inhibits HER2 cleavage, preceding antibody-induced receptor downmodulation, and this effect might contribute to its antitumor activity in some cancers. In vivo, trastuzumab inhibits angiogenesis and induces antibody-dependent cellular cytotoxicity. A limitation of trastuzumab is that its activity is largely restricted to breast cancers with the highest level of HER2 overexpression or HER2 gene amplification. However, there is a large population of breast cancers and of many other tumors that have low or moderate HER2 expression. In such tumors, HER2 functions as a preferred coreceptor to form heterodimers with HER1 (EGFR), HER3 or HER4. For this reason, a humanized monoclonal antibody, called 2C4, that targets the role of HER2 as a coreceptor is under active development. 2C4 binds to a different epitope of HER2 ectodomain than trastuzumab and sterically hinders HER2 recruitment in heterodimers with other HER receptors. This results in the inhibition of signalling by HER2-based heterodimers both in cells with low and high HER2 expression. In vitro and in vivo antitumor activity has been reported in a range of breast and prostate tumor models. Therefore, 2C4 may have potential against a wide variety of solid tumors. Phase I trials are underway.
跨膜酪氨酸激酶受体HER家族由四个成员组成，即HER1至HER4。HER2是一种孤儿配体受体，在许多人类肿瘤中表达，在25%-30%的乳腺癌中过度表达。HER2通过形成异二聚体来放大HER家族其他受体提供的信号。HER2在HER信号网络中的关键作用促使了用于癌症治疗的抗HER2单克隆抗体（MAb）的研发。特别是，人源化单克隆抗体曲妥珠单抗（赫赛汀）对HER2过度表达的人乳腺肿瘤细胞具有抗肿瘤活性，并广泛用于治疗HER2过度表达的乳腺癌女性患者。曲妥珠单抗可诱导HER2受体下调，从而抑制关键信号通路（即ras-Raf-MAPK和PI3K/Akt），并通过诱导p27/Cdk2复合物的形成来阻断细胞周期进程。曲妥珠单抗还能在抗体诱导的受体下调之前抑制HER2的裂解，这种作用可能有助于其在某些癌症中的抗肿瘤活性。在体内，曲妥珠单抗可抑制血管生成并诱导抗体依赖性细胞毒性。曲妥珠单抗的一个局限性在于其活性主要局限于HER2过度表达或HER2基因扩增水平最高的乳腺癌。然而，有大量乳腺癌以及许多其他肿瘤的HER2表达水平较低或中等。在这类肿瘤中，HER2作为首选共受体与HER1（表皮生长因子受体，EGFR）、HER3或HER4形成异二聚体。因此，一种针对HER2作为共受体作用的人源化单克隆抗体2C4正在积极研发中。2C4与曲妥珠单抗结合HER2胞外域的不同表位，在空间上阻碍HER2与其他HER受体形成异二聚体。这导致在HER2表达水平低和高的细胞中基于HER2的异二聚体信号传导均受到抑制。在一系列乳腺癌和前列腺癌肿瘤模型中已报道了2C4的体外和体内抗肿瘤活性。因此，2C4可能对多种实体瘤具有潜在作用。I期试验正在进行中。
