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ErbB2 cellular signaling pathways and lapatinib mechanism of action. ErbB2 (HER2) is a transmembrane tyrosine kinase activated by dimerization with itself or other ErbB proteins (i.e. ErbB1, ErbB3). Binding of ErbB1 ligands to ErbB1 stimulates heterodimerization with ErbB2 and activation of downstream signaling pathways, including PI3K, Akt protein kinase and mTOR, resulting in an increase in cell proliferation. The PTEN protein has tumor suppressor activity in this signaling pathway and loss of PTEN, as well as upregulation of IGF-1R signaling, is associated with trastuzumab resistance. Lapatinib blocks the activation of the ErbB2 signaling pathway by inhibiting the intracellular tyrosine kinase of ErbB1 and ErbB2 and may circumvent trastuzumab resistance associated with upregulation of IGF-1R signaling. Lapatinib also binds to the p95 truncated variant of ErbB2 (p95 ErbB2) and inhibits cell proliferation in trastuzumab-resistant cells expressing p95 ErbB2. ErbB1, human epidermal growth factor receptor 1 (EGFR); ErbB2, human epidermal growth factor receptor 2 (ErbB2); IGF-1R, insulin-like growth factor-1 receptor; PI3K, phosphatidylinositol-3-kinase; PTEN, Phosphatase and tensin homolog deleted on chromosome 10; mTOR, mammalian target of rapamycin.
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HYQ084F1: ErbB2 cellular signaling pathways and lapatinib mechanism of action. ErbB2 (HER2) is a transmembrane tyrosine kinase activated by dimerization with itself or other ErbB proteins (i.e. ErbB1, ErbB3). Binding of ErbB1 ligands to ErbB1 stimulates heterodimerization with ErbB2 and activation of downstream signaling pathways, including PI3K, Akt protein kinase and mTOR, resulting in an increase in cell proliferation. The PTEN protein has tumor suppressor activity in this signaling pathway and loss of PTEN, as well as upregulation of IGF-1R signaling, is associated with trastuzumab resistance. Lapatinib blocks the activation of the ErbB2 signaling pathway by inhibiting the intracellular tyrosine kinase of ErbB1 and ErbB2 and may circumvent trastuzumab resistance associated with upregulation of IGF-1R signaling. Lapatinib also binds to the p95 truncated variant of ErbB2 (p95 ErbB2) and inhibits cell proliferation in trastuzumab-resistant cells expressing p95 ErbB2. ErbB1, human epidermal growth factor receptor 1 (EGFR); ErbB2, human epidermal growth factor receptor 2 (ErbB2); IGF-1R, insulin-like growth factor-1 receptor; PI3K, phosphatidylinositol-3-kinase; PTEN, Phosphatase and tensin homolog deleted on chromosome 10; mTOR, mammalian target of rapamycin.

Mentions: Lapatinib (GW572016) is a unique, orally bioavailable, small-molecule dual tyrosine kinase inhibitor developed by GlaxoSmithKline that targets tumor cells overexpressing both human epidermal growth factor receptor (EGFR; ErbB1) and ErbB2 tyrosine kinases (5). Lapatinib inhibition of ErbB1 and ErbB2 kinase activity prevents the activation of downstream cellular signals that promote tumor cell survival and proliferation (6–8) (Fig. 1). Using a rational drug design approach, more than 3200 quinazoline and quinazoline-like compounds with potential tyrosine kinase activity were screened and assayed. Lapatinib was eventually selected from these compounds as it was a selective and potent inhibitor of ErbB1 and ErbB2 that had predictable oral bioavailability and acceptable in vivo toxicity in the targeted patient population (9). First-in-human studies with lapatinib were initiated in 2001; in 2007 lapatinib was approved in the USA for use in combination with capecitabine for the treatment of ErbB2+ advanced or metastatic breast cancer in patients who had received previous treatment including an anthracycline, a taxane and trastuzumab (10) (Fig. 2). Additional approvals for this indication have been granted in 90 more countries, including Japan. The clinical development of lapatinib is continuing with attention focused on ErbB2+ breast cancer as well as other cancers that overexpress ErbB2.Figure 1.

Management of ErbB2-positive Breast Cancer: Insights from Preclinical and Clinical Studies with Lapatinib

Vogel C, Chan A, Gril B, Kim SB, Kurebayashi J, Liu L, Lu YS, Moon H - Jpn. J. Clin. Oncol. (2010)

Bottom Line: Lapatinib, in combination with chemotherapeutic agents, such as capecitabine, provides clinical benefits to patients with ErbB2+ breast cancer, including patients who develop progressive disease on trastuzumab.Encouraging results have also emerged regarding the synergistic effects of lapatinib in combination with other agents for the treatment of ErbB2+ breast cancer.Collectively, these results indicate that the judicious use of lapatinib, an effective oral therapy with a manageable toxicity profile, can enhance the management of patients with ErbB2+ breast cancer.

Affiliation: Sylvester Comprehensive Cancer Center at Deerfield Beach, University of Miami Miller School of Medicine, 1192 East Newport Center Drive, Deerfield Beach, FL 33442, USA. drcvogel@aol.com

ABSTRACT
The management of human epidermal growth factor receptor 2-positive (ErbB2+) breast cancer is challenging; patients with ErbB2+ breast tumors have more aggressive disease and a poor prognosis. The increasing incidence of breast cancer in Asia and the limitations of existing treatments pose additional challenges. In this review, we summarize the preclinical and clinical evidence that indicates how lapatinib, a novel inhibitor that targets the human epidermal growth factor receptor (ErbB1) and ErbB2 may help clinicians address four particularly challenging issues in the management of ErbB2+ breast cancer. These issues are: (i) trastuzumab therapy failure, (ii) development of central nervous system metastases, (iii) minimizing toxicity and (iv) selecting the most appropriate partners (chemotherapy and non-chemotherapy) for combination therapy with lapatinib. Lapatinib, in combination with chemotherapeutic agents, such as capecitabine, provides clinical benefits to patients with ErbB2+ breast cancer, including patients who develop progressive disease on trastuzumab. Lapatinib, in combination with non-chemotherapeutic agents, such as letrozole, may also provide a chemotherapy-free treatment option for postmenopausal patients with estrogen receptor-positive/ErbB2+ metastatic breast cancer. Encouraging results have also emerged regarding the synergistic effects of lapatinib in combination with other agents for the treatment of ErbB2+ breast cancer. Promising findings have also been reported for the use of lapatinib to prevent and treat central nervous system metastases. Collectively, these results indicate that the judicious use of lapatinib, an effective oral therapy with a manageable toxicity profile, can enhance the management of patients with ErbB2+ breast cancer.

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