Herceptin

Herceptin (or Trastuzumab) is an anti-cancer therapy that acts on the erbB2 receptor.

Amplification of ErbB2 occurs in 30% of early-stage breast cancers (Bange et al., 2001). It encodes the transmembrane tyrosine kinase p185-erbB2 glycoprotein. Although the signaling pathways induced by the erbB2 receptor are incompletely characterized, it is thought that activation of the PI3K/Akt pathway is important. This pathway is normally associated with mitogenic signaling involving the MAPK pathway. In cancer growth producing signals from erbB2 are constitutively transmitted, promoting invasion, survival and angiogenesis of cells (Ménard et al., 2003). Furthermore overexpression can also confer therapeutic resistance to cancer therapies. Kute et al. (2004) suggest that the prime mechanism that causes increase in proliferation speed is due to induction of p27Kip1, an inhibitor of cdk2 and of cell proliferation, to remain in the cytoplasm instead of translocation in to the nucleus. This is caused by phosphorylation by Akt.

Herceptin is a monoclonal antibody which binds to its extracellular segment of the erbB2 receptor. Cells treated with Herceptin undergo arrest during the G1 phase of the cell cycle and experience a reduction in proliferation. It has been suggested that Herceptin induces some of its effect by downregulation of erbB2 leading to disruption of receptor dimerization and signaling through the downstream PI3K cascade. P27Kip1 is then not phosphorylated and is able to enter the nucleus and inhibit cdk2 activity, causing cell cycle arrest (Kute et al., 2004). Also Herceptin suppresses angiogenesis by induction of antiangiogenic factors and repression of proangiogenic factors. It is thought that a contribution to the unregulated growth observed in cancer could be due to proteolytic cleavage of erbB2 that results in the release of the extracellular domain. Herceptin has been shown to inhibit erbB2 ectodomain cleavage in breast cancer cells (Albenall et al., 2003). There may be other undiscovered mechanisms by which Herceptin induces regression in cancer.

Herceptin has had a “major impact in the treatment of HER2-positive metastatic breast cancer” (Tan and Swain, 2002). In combination with chemotherapy Herceptin has been shown to increase both survival and response rate in comparison to Herceptin alone (Nahta and Esteva1, 2003). It is possible to determine the 'erbB2 status' of a tumour, which can be used to predict efficacy of treatment with Herceptin. If it is determined that a tumour is overexpressing the erbB2 oncogene then a patient is eligible for treatment with Herceptin (Yu and Hung, 2000). It is surprising that although erbB2 has great affinity for the receptor and the fact that such a high dose can be administered (due to its low toxicity) 70% of patients do not respond to treatment. In fact resistance is developed rapidly on treatment of virtually all patients. It is suggested that a mechanism of resistance is the lack p27Kip1 translocation to the nucleus in some strains, enabling cdk2 to induce cell proliferation (Kute et al., 2000).

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Kute T, Lack CM, Willingham M, Bishwokama B, Williams H, Barrett K, Mitchell T, Vaughn JP. (2004). Development of Herceptin resistance in breast cancer cells. Cytometry, 57A:86-93
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Yu D, Hung M. (2000). Overexpression of ErbB2 in cancer and ErbB2-targeting strategies. Oncogene, 19:6115-6121