Mechanisms of action of the HER dimerization inhibitor pertuzumab alone or with trastuzumab

Joan Albanell, Sonia Servitja, Ana Rovira, Federico Rojcf, Ignasi Tusquets

Research output: Contribution to journalReview articleResearchpeer-review

1 Citation (Scopus)


Objective of the review: Pertuzumab (2C4, Perjeta™) is a first drug of a novel class of therapeutic antibodies known as HER dimerization inhibitors. The goal of this article is to review the biology of HER2-positive breast cancer and the distinct but complementary mechanisms of action of pertuzumab and trastuzumab (Herceptin™). Methodology: MEDLINE search of pertuzumab or 2C4 followed by critical review of key papers. Main Results: Pertuzumab targets an extracellular domain of HER2 -the heterodimerization loop in sub-domain II of HER2 - that, unlike trastuzumab, results in sterical hindrance of HER2 for recruitment into HER-ligand complexes, allowing an effective disruption of HER2 ligand-dependent activation. This effect is crucial since the key oncogenic unit in HER2-positive breast cancer is a complex of HER2 and HER3 that signals to PI3K and Akt. This ligand-dependent dimerization cannot be disrupted by trastuzumab, but is efficiently blocked by pertuzumab. Interestingly, trastuzumab prevents ligand-independent HER2 dimerization and also has other specific effects such as prevention of HER2 cleavage and antiangiogenic actions that mediate antitumor effects. Both antibodies elicit antibody dependent cellular cytotoxicity. Preclinically, pertuzumab combined with trastuzumab was superior to each antibody given alone in HER2-overexpressing cancers and is also effective in tumor xenografts progressing to trastuzumab alone. Clinical studies confirm this observation and the combination of trastuzumab plus pertuzumab has been recently approved by the FDA for advanced HER2-positive breast cancer. Conclusions: The key difference between pertuzumab and the traditional anti-HER2 antibody trastuzumab is that they bind to different epitopes of the HER2 ectodomain, leading to distinct and complementary mechanisms of action. The combination of the two antibodies is significantly superior to each agent alone, preclinically and clinically, in HER2-positive breast cancer.
Original languageEnglish
Pages (from-to)24-32
JournalCancer and Chemotherapy Reviews
Issue number1
Publication statusPublished - 1 Jan 2013


  • HER dimerization inhibitors
  • HER2
  • HER3
  • Pertuzumab
  • Trastuzumab


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