Mechanisms of Disease: understanding resistance to HER2-targeted therapy in human breast cancer

Abstract

Trastuzumab is a monoclonal antibody targeted against the human epidermal growth factor receptor (HER) 2 tyrosine kinase receptor, which is overexpressed in approximately 25% of invasive breast cancers. The majority of patients with metastatic breast cancer who initially respond to trastuzumab, however, demonstrate disease progression within 1 year of treatment initiation. Preclinical studies have indicated several molecular mechanisms that could contribute to the development of trastuzumab resistance. Increased signaling via the phosphatidylinositol 3-kinase/Akt pathway could contribute to trastuzumab resistance because of activation of multiple receptor pathways that include HER2-related receptors or non-HER receptors such as the insulin-like growth factor 1 receptor, which appears to be involved in a cross-talk with HER2 in resistant cells. Additionally, loss of function of the tumor suppressor PTEN gene, the negative regulator of Akt, results in heightened Akt signaling that leads to decreased sensitivity to trastuzumab. Decreased interaction between trastuzumab and its target receptor HER2, which is due to steric hindrance of HER2 by cell surface proteins such as mucin-4 (MUC4), may block the inhibitory actions of trastuzumab. Novel therapies targeted against these aberrant molecular pathways offer hope that the effectiveness and duration of response to trastuzumab can be greatly improved.

Effects of the combined blockade of EGFR and ErbB-2 on signal transduction and regulation of cell cycle regulatory proteins in breast cancer cells

“…In particular, we have shown that blockade of both tyrosine kinases causes a prolonged inhibition of MAPK and AKT activation as compared with inhibition of a single receptor. Both these pathways are involved in the intrinsic and acquired resistance of breast cancer cells to anti-EGFR and anti-ErbB-2 drugs [26,31,32]. Interestingly, our findings show that following treatment with trastuzumab an increase in the levels of activation of MAPK is observed (Figure 1).…”

Clinical relevance of ErbB-2/HER2 nuclear expression in breast cancer

“…This network would be involved in growth, metastasis and/or response to anti-ErbB-2 therapies, such as trastuzumab. Blockage of MembErbB-2 capacity to activate cytoplasmic signaling cascades is one of the mechanisms of trastuzumab action [5,33,34]. Therefore, a likely explanation to trastuzumab resistance could be ErbB-2 nuclear presence and function as a transcriptional regulator.…”

“…At present, the recombinant humanized anti-ErbB-2 monoclonal antibody trastuzumab is successfully used for treatment of MembErbB-2-positive breast cancer in the metastatic and the adjuvant settings [3,4]. However, a significant percentage of tumors display primary or acquired trastuzumab resistance [5]. Notably, the dogma of ErbB-2 action as a membrane tyrosine kinase which induces the activation of mitogenic signaling pathways to promote breast cancer growth [1], has been challenged by the demonstration that MembErbB-2 migrates to the nuclear compartment, where it acts as a transcription factor (TF) [6].…”

Antagonism of the human epidermal growth factor receptor family controls disease severity in murine collagen‐induced arthritis

“…However, some cancer cells were resistant to herstatin treatment, which could be explained by heterodimerization of ligand-activated ErbB receptors with members of the RTK family of receptors other than HER-2 (38). Pertuzumab, another recombinant humanized HER-2 monoclonal antibody, sterically blocked heterodimerization of HER-2 with other family member receptors and is currently being investigated in clinical trials (39).…”