Mechanisms Underlying the Action and Synergism of Trastuzumab and Pertuzumab in Targeting HER2-Positive Breast Cancer

Abstract

Human epidermal growth factor receptor (HER) 2 (HER2) is overexpressed in 20⁻30% of breast cancers. HER2 is a preferred target for treating HER2-positive breast cancer. Trastuzumab and pertuzumab are two HER2-targeted monoclonal antibodies approved by the Food and Drug Administration (FDA) to use as adjuvant therapy in combination with docetaxel to treat metastatic HER2-positive breast cancer. Adding the monoclonal antibodies to treatment regimen has changed the paradigm for treatment of HER2-positive breast cancer. Despite improving outcomes, the percentage of the patients who benefit from the treatment is still low. Continued research and development of novel agents and strategies of drug combinations is needed. A thorough understanding of the molecular mechanisms underlying the action and synergism of trastuzumab and pertuzumab is essential for moving forward to achieve high efficacy in treating HER2-positive breast cancer. This review examined and analyzed findings and hypotheses regarding the action and synergism of trastuzumab and pertuzumab and proposed a model of synergism based on available information.

Keywords: HER family receptors; HER2; breast cancer; mechanisms; pertuzumab; synergism; trastuzumab.

Figure 1

The activation of HER receptors and the downstream signaling cascades. Four members of HER receptors interact with 11 ligands, which results in the formation and the activation of 10 different homo- and heterodimers. Activated HER receptors promote many signaling cascades affecting many key biological outcomes.

Figure 2

The potential mode of action of trastuzumab and pertuzumab. (A) Five mechanism have been proposed and partially tested regarding the action of trastuzumab. (B) The mechanism of pertuzumab is likely through the inhibition of HER2 dimerization and activation.

Figure 3

Proposed models illustrating the synergism of trastuzumab and pertuzumab. (A) A favored theory by assuming the distinctive action of trastuzumab and pertuzumab on HER2 homo- and heterodimers with or without ligand. (B) Hypothesis based on computational analysis, which suggests cooperative interactions between the two antibodies.

Figure 4

Model proposed in this review by including more recent data. Pertuzumab acts to inhibit the classical HER2-mediated cell-signaling cascades by blocking HER2 dimerization. Trastuzumab acts through ADCC and the inhibition of HER2 cleavage.