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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.

Key Points

  • Based on the results of the phase III trials, trastuzumab can increase median survival when combined with standard chemotherapy in patients with breast cancer

  • Mechanisms of action of trastuzumab include inhibition of HER2 extracellular domain proteolysis, disruption of downstream signaling pathways, G1 cell-cycle arrest, inhibition of DNA repair, suppression of angiogenesis, and induction of antibody-dependent cellular cytotoxicity

  • Potential mechanisms of trastuzumab resistance include altered receptor-antibody interaction, increased cell signaling from other HER receptors, increased Akt activity, reduced PTEN level, reduced p27kip1, and increased IGF-IR signaling

  • There is an urgent need to identify biomarkers to guide anti-HER-2 therapy in patients who develop progressive metastatic breast cancer while receiving trastuzumab, and to identify combination therapies using novel anti-HER-2 agents

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Figure 1: Proposed mechanisms of trastuzumab resistance.

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Acknowledgements

The authors wish to acknowledge funding from the American Association for Cancer Research-Amgen, Inc. Fellowship in Clinical/Translational Cancer Research (R Nahta), K23 CA82119 (FJ Esteva), the University Cancer Foundation Fund at the University of Texas MD Anderson Cancer Center (FJ Esteva, R Nahta), the Nellie B Connally Breast Cancer Research Fund for supporting the Breast Cancer Translational Research Laboratory at MD Anderson Cancer Center, and NIH Cancer Center Support Grant CA 16672-27.

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Correspondence to Rita Nahta or Francisco J Esteva.

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LA Liotta is a co-inventor on patents that describe technologies that are covered in this manuscript. By law, I am entitled to receive royalties on any license taken. EF Petricoin is an inventor on patents that describe technologies that are covered in this manuscript. By law, I am entitled to receive royalties on any license taken.

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Nahta, R., Yu, D., Hung, MC. et al. Mechanisms of Disease: understanding resistance to HER2-targeted therapy in human breast cancer. Nat Rev Clin Oncol 3, 269–280 (2006). https://doi.org/10.1038/ncponc0509

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