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Mechanisms of disease: understanding resistance to HER2-targeted therapy in human breast cancer.
Nat Clin Pract Oncol. 2006 May; 3(5):269-80.NC

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.

Authors+Show Affiliations

Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston 77030-4009, USA. rnahta@mdanderson.orgNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review

Language

eng

PubMed ID

16683005

Citation

Nahta, Rita, et al. "Mechanisms of Disease: Understanding Resistance to HER2-targeted Therapy in Human Breast Cancer." Nature Clinical Practice. Oncology, vol. 3, no. 5, 2006, pp. 269-80.
Nahta R, Yu D, Hung MC, et al. Mechanisms of disease: understanding resistance to HER2-targeted therapy in human breast cancer. Nat Clin Pract Oncol. 2006;3(5):269-80.
Nahta, R., Yu, D., Hung, M. C., Hortobagyi, G. N., & Esteva, F. J. (2006). Mechanisms of disease: understanding resistance to HER2-targeted therapy in human breast cancer. Nature Clinical Practice. Oncology, 3(5), 269-80.
Nahta R, et al. Mechanisms of Disease: Understanding Resistance to HER2-targeted Therapy in Human Breast Cancer. Nat Clin Pract Oncol. 2006;3(5):269-80. PubMed PMID: 16683005.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mechanisms of disease: understanding resistance to HER2-targeted therapy in human breast cancer. AU - Nahta,Rita, AU - Yu,Dihua, AU - Hung,Mien-Chie, AU - Hortobagyi,Gabriel N, AU - Esteva,Francisco J, PY - 2005/10/01/received PY - 2006/02/07/accepted PY - 2006/5/10/pubmed PY - 2006/10/13/medline PY - 2006/5/10/entrez SP - 269 EP - 80 JF - Nature clinical practice. Oncology JO - Nat Clin Pract Oncol VL - 3 IS - 5 N2 - 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. SN - 1743-4254 UR - https://www.unboundmedicine.com/medline/citation/16683005/Mechanisms_of_disease:_understanding_resistance_to_HER2_targeted_therapy_in_human_breast_cancer_ L2 - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=linkout&SEARCH=16683005.ui DB - PRIME DP - Unbound Medicine ER -