The role of HER2 in cancer therapy and targeted drug delivery

Abstract

HER2 is highly expressed in a significant proportion of breast cancer, ovarian cancer, and gastric cancer. Since the discovery of its role in tumorigenesis, HER2 has received great attention in cancer research during the past two decades. Successful development of the humanized monoclonal anti-HER2 antibody (Trastuzumab) for the treatment of breast cancer further spurred scientists to develop various HER2 specific antibodies, dimerization inhibitors and kinase inhibitors for cancer therapy. On the other hand, the high expression of HER2 and the accessibility of its extracellular domain make HER2 an ideal target for the targeted delivery of anti-tumor drugs as well as imaging agents. Although there is no natural ligand for HER2, artificial ligands targeting HER2 have been developed and applied in various targeted drug delivery systems. The emphasis of this review is to elucidate the roles of HER2 in cancer therapy and targeted drug delivery. The structure and signal pathway of HER2 will be briefly described. The role of HER2 in tumorigenesis and its relationship with other tumor markers will be discussed. For the HER2 targeted cancer therapy, numerous strategies including the blockage of receptor dimerization, inhibition of the tyrosine kinase activity, and interruption of the downstream signal pathway will be summarized. For the targeted drug delivery to HER2 positive tumor cells, various targeting ligands and their delivery systems will be described in details.

Fig 1

The structures of HER2 ECD and its complex with Pertuzumab (PDB Code 1S78) and Trastuzumab fragment (PDB Code 1N8Z). A) The diagram of HER2 ECD. The domain I was highlighted in green, domain II in brown, domain III in lightyellow, and domain IV in cyan. The dimerization arm in domain II is also indicated. B) Fab of Pertuzumab (palegreen) binds to the dimerization arm of HER2 receptor and inhibits its dimerization with other HER receptors. C) The complex of HER2 ECD with the Fab of Trastuzumab (palegreen). The Trastuzumab Fab binds to the domain IV of HER2 ECD. [Fig 1 was prepared using the program Pymol (DeLano, W.L. The PyMOL Molecular Graphics System (2002) DeLano Scientific, San Carlos, CA, USA)]

Fig 2

The sequence and structure of HER receptors’ transmembrane domain. A) The sequences of HER receptors transmembrane domains (~23 residues), the dimerization motifs are highlighted. Sternberg-Gullick motif is colored in red and G***G motif in yellow. The residue in blue presents a Val/Ile single nucleotide polymorphism. B) The surface of a HER2 transmembrane domain homodimer (PDB Code 2JWA). The dimerization is triggered by the strong association forces between Sternberg-Gullick motifs (red) and G***G motifs (yellow). (Fig. 2A is adapted from Sarel J. F. et al A putative molecular-activation switch in the transmembrane domain of erbB2 PNAS 2002; 99:15937–15940. Copyright permission will be requested.) [Figure 2B was prepared using the program Pymol (DeLano, W.L. The PyMOL Molecular Graphics System (2002) DeLano Scientific, San Carlos, CA, USA)]

Fig 3

The HER2 signaling pathway. Following ligand dependent activation of HER receptor, HER2 dimerizes with the activated HER receptor which results in tyrosine residues phosphorylation and signal transduction. PLCγ, PI3K and MAPK are the most common signaling cascades, whereas PI3K and MAPK are the major pathways involved in tumor growth and antiapoptosis.

Fig 4

Various strategies for targeted drug delivery to HER2 positive cells. A) Anti-HER2 antibody mediated nanoscaled system. B) Anti-HER2 Antibody-Drug Conjugate (ADC). C) Anti-HER2 antibody fusion protein can be used for nucleic acids delivery. D) Radionuclide is conjugated to anti-HER2 affibody for tumor imaging. E) Affibody conjugated drug delivery system. F) Anti-HER2 peptide mediated drug delivery.

Fig 5

Structures of Trastuzumab-maytansinoid (Tmab-DM1). Maytansinoid was conjugated to Trastuzumab via various disulfide bonds and thioether bonds. While Tmab-SSNPP-DM4 and Tmab-MCC-DM1 showed the highest stablility, Tmab-MCC-DM1 exhibited more potent activity in vivo. (Adapted from Lewis Phillips GD et al Targeting HER2-Positive Breast Cancer with Trastuzumab-DM1, an Antibody–Cytotoxic Drug Conjugate Cancer Res 2008; 68: (22). 9280–9290. Copyright permission will be requested.)