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Fig. 6 | BMC Cancer

Fig. 6

From: A novel treatment strategy for lapatinib resistance in a subset of HER2-amplified gastric cancer

Fig. 6

A schematic diagram showing potential HER2-related signaling pathways and action mechanisms of various inhibitors in HER2-amplified GC. Heterodimerization of HER2 with other HER family members (such as EGFR, HER3, HER4) result in tyrosine kinase activation with the subsequent signaling cascade, including members of MAPK and PI3K/AKT/mTOR pathways. As a result of these signaling pathways activation, different nuclear factors are recruited and modulate the transcription of different genes involved in cell-cycle progression, proliferation, and survival. Trastuzumab inhibits HER2 by targeting its extracellular domain, whereas lapatinib inhibits both HER2 and EGFR by inhibiting the intracellular tyrosine kinases. HER2 targeted therapy could be interrupted by re-activation MAPK and PI3K/AKT/mTOR pathways by compensatory activation of MET, IGF-RI, HER3 or loss of function mutations of tumor suppressor genes such as CSK, PTEN, NF1. In addition, drug resistance could be conferred by loss of function mutations of downstream genes such as KEAP1 and BAX by dysregulation of cellular antioxidants, xenobiotic detoxification enzymes and apoptosis, respectively. Lapatinib combining with lapatinib, SRC inhibitor AZD0530, PI3K inhibitor copanlisib, mTOR inhibitor rapamycin or MEK inhibitor trametinib could counteract the resistance at different level, respectively. A combinational treatment strategy with lapatinib, copanlisib and trametinib is demonstrated more effective for HER2 amplified GC with CSK, PTEN, NF1and KEAP1 mutations in this study

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