ErbB2 cellular signaling pathways and lapatinib mechanism of action

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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Management of ErbB2-positive Breast Cancer: Insights from Preclinical and Clinical Studies with Lapatinib. (2010) Charles Vogel, et al. Jpn J Clin Oncol. 2010 Nov;40(11):999-1013. Figure: F1. All organisms Drosophila melanogaster Homo sapiens

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