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- Title
A dual tyrosine kinase inhibitor lapatinib suppresses overexpression of matrix metallopeptidase 1 (MMP1) in endometrial cancer.
- Authors
Lin, Chiao-Yun; Chao, Angel; Wang, Tzu-Hao; Hsueh, Swei; Lee, Yun-Shien; Wu, Tzu-I; Chao, An-Shine; Huang, Huei-Jean; Chou, Hung-Hsueh; Chang, Ting-Chang; Lai, Chyong-Huey
- Abstract
Endometrial cancers have been recently molecularly characterized; amplifications of human epidermal growth factor receptor 2 (HER2) were seen in 25 % of the serous-like tumors, and mutations in the PI(3)K/AKT pathways were seen in 93 % of endometrioid tumors. These new findings about endometrial cancer suggest a potential for targeted therapy with lapatinib, a dual inhibitor of epidermal growth factor receptor and HER2 tyrosine kinases. However, the clinical efficacy of lapatinib in phase II clinical trials for the treatment of endometrial cancers was only minimal. In this study, we investigated the signaling changes induced by lapatinib in endometrial cancer, which may improve its therapeutic efficacy in molecularly selected patient groups. We identified one of the final molecular targets of lapatinib to be interstitial collagenase, matrix metallopeptidase 1 (MMP1). Lapatinib suppresses MMP1 through EGFR and HER2, and their downstream ERK and AKT signaling pathways. We also found that the activating protein-1 binding site of MMP1 promoter is required for its transcriptional activation, which may be unique for endometrial cancers. Our results also showed that forced expression of active ERK or active AKT mutants rescued MMP1 expression from lapatinib suppression, further suggesting the importance of molecular selection to find appropriate patients with endometrial cancer for future clinical trials with any targeted therapies. Key message:
- Subjects
LAPATINIB; PROTEIN-tyrosine kinases; PEPTIDASE regulation; TREATMENT of endometrial cancer; EPIDERMAL growth factor receptors; TREATMENT of endometriosis
- Publication
Journal of Molecular Medicine, 2014, Vol 92, Issue 9, p969
- ISSN
0946-2716
- Publication type
Article
- DOI
10.1007/s00109-014-1163-0