Abstract
The past decade of research into HER2-overexpressing breast cancer has provided significant insight into the mechanisms by which HER2 signaling drives tumor progression, as well as potential mechanisms by which cancer cells escape the anticancer activity of HER2-targeted therapy. Many of these preclinical findings have been translated into clinical development, resulting in novel combinations of HER2-targeted therapies and combinations of trastuzumab plus inhibitors of resistance pathways. In this paper, we will discuss proposed mechanisms of trastuzumab resistance, including epitope masking, cross signaling from other cell surface receptors, hyperactive downstream signaling, and failure to induce antibody-dependent cellular cytotoxicity. In addition, we will discuss the molecular mechanisms of action of dual HER2 inhibition, specifically the combination of trastuzumab plus lapatinib or trastuzumab with pertuzumab. We will also discuss data supporting therapeutic combinations of trastuzumab with agents targeted against molecules implicated in trastuzumab resistance. The roles of insulin-like growth factor-I receptor and the estrogen receptor are discussed in the context of resistance to HER2-targeted therapies. Finally, we will examine the major issues that need to be addressed in order to translate these combinations from the bench to the clinic, including the need to establish relevant biomarkers to select for those patients who are most likely to benefit from a particular drug combination.
Highlights
The HER2 receptor tyrosine kinase gene is amplified and overexpressed at the protein level in 20–30% of metastatic breast cancers
HER2-overexpressing breast cancers that have progressed on trastuzumab show particular sensitivity to PI3K inhibition [25, 105], indicating that this downstream signaling pathway plays a critical role in driving progression of HER2-postive disease
We previously showed that combining trastuzumab and pertuzumab in HER2-positive BT474 cells resulted in synergistic inhibition of proliferation, increased apoptosis, disruption of HER2-HER3 dimerization, and reduced Akt phosphorylation [154]
Summary
The HER2 (erbB2/neu) receptor tyrosine kinase gene is amplified and overexpressed at the protein level in 20–30% of metastatic breast cancers. In combination with cytotoxic chemotherapy, trastuzumab has revolutionized treatment and clinical outcome for patients whose breast tumors express high levels of the HER2 protein. ISRN Oncology result in development of fibrosarcomas when injected into mice [1] Sera from these mice immunoprecipitated a 185kiloDalton phosphoprotein from cells transfected with the neuroblastoma-derived DNA [1]. HER2 kinase mutations have been detected in some cancers including lung adenocarcinomas [11], mutation of HER2 does not appear to be required to confer transforming potential in mammary epithelial cells, as the amplified HER2 found in overexpressing tumors is generally wildtype
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