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The off-target activities of lapatinib : Achilles` shield or heel?
Wei-Chien Huang(黃偉謙) 한의병리학회 2015 대한동의병리학회 학술대회논문집 Vol.2015 No.10
Lapatinib, a dual epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2) kinase inhibitor, showed clinical benefits in advanced HER2-positive breast cancer patients. Because EGFR overexpression was frequently found in triple-negative breast cancers (TNBCs), the antitumor activity of lapatinib in such diseases was also tested. However, the results showed a worse event-free survival rate. Recently, our studies demonstrated that lapatinib facilitated axillary and lung metastases of triple-negative MDA-MB-231 breast cancer cells without affecting their viability, leading to worse survival in orthotopic xenograft mice. The lapatinib-increased motility was attributed by its off target effects on the downregulation of microRNA-7 and the subsequent overexpression of cyclooxygenase-2 (COX-2) and interleukin-6 (IL-6) through NF- B and Raf-1 activation respectively. Unexpectedly, lapatinib-induced NF- B activation and HDAC expression render TNBC cells more sensitive to proteasome inhibitor and HDAC inhibitor, showing potential partners for combination therapies with with lapatinib to benefit TNBC patients.