Targeting the HER2 oncoprotein: lessons learned from quantitative cytometry
Department of Biophysics and Cell Biology, and MTA-DE Cell Biology and Signaling Research Group, University of Debrecen, Hungary
Breast cancers, and malignant tumors of several other organs (gastric, ovary, brain) often overexpress HER2 (neu, ErbB2), a receptor tyrosine kinase of the epidermal growth factor receptor family. This is often correlated with rapid clinical progression, resistance to radio or chemotherapy, and, overall, bad prognosis. Since HER2 is not, or weakly expressed in healthy human tissues, it can be considered an ideal target of antitumor therapy. In coherency with this, the first humanized antibody against solid tumors was trastuzumab (Herceptin), targeting HER2. Although trastuzumab treatment of HER2 positive tumors has shown considerable success, resistance occurs in a significant fraction of patients, both from the start of treatment and evolving during treatment. Earlier we have shown that an important cause of this resistance is the massive extracellular matrix evolved by tumors. Considering that the antibody can mainly act by down-regulating HER2 or by recruiting antibody dependent cellular cytotoxicity (ADCC), various biochemical and immunological approaches can be proposed for decreasing or obviating the resistance against trastuzumab treatment.
Since HSP-90 serves to retain HER2 in a well-folded, but inactive conformation, the geldanamycin derivative 17-AAG can be used to enhance HER2 dimerization, consequential down-regulation, and thus to decrease proliferation of trastuzumab resistant breast cancer cells. However, this comes at a price, since HER2 activation is also increased transiently, and side effects in the clinic can be significant.
Recently, the myxobacterial antibiotic archazolid, a potent inhibitor of the lysosomal V-ATPase has been produced synthetically, which enabled widespread testing. It appears that archazolid interferes with the regular recirculation of HER2, results in its retention in phagolysosomes and autophagosomes, decreases HER2 phosphorylation, and inhibits the growth of xenograft tumors. Yet, its bioavailability needs to be improved to make it a viable option for adjuvant therapy.
Trastuzumab can also be combined with other HER2-targeted antibodies, such as pertuzumab, which increases the resistance-free period in tumor-bearing mice. The beneficial, additive effect of the combination is related to the fact that maximal approved clinical doses of either antibody alone do not saturate ADCC. Thus, it is recommended that both in the adjuvant and neoadjuvant setting the two antibodies are applied in combination from the start.
Finally, it is possible to build a chimeric antigen receptor (CAR) containing trastuzumab scFv for MHC non-restricted target recognition, and important motifs of the T cell receptor and co-signaling molecules. This, when transduced into naive T cells, enables the destruction of HER2 positive tumors by the CAR T cells that perform active reconnaissance, even when the therapeutic antibody cannot anymore penetrate the extracellular matrix with passive diffusion.