Abstract A73: AMPK activation mediates dasatinib-induced EGFR degradation and apoptosis in head and neck cancer

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a worldwide disease with aggressive course and dismal outcome. Dasatinib, a Bcr-abl and Src in hibitor, has been approved clinically for CML and shown activities against solid tumors in vitro. In our recent work, degradation of epidermal growth factor receptor (EGFR) plays a role in dasatinib-induced apoptosis in HNSCC cells. We further explored the mechanism of this event. ER stress was induced by dasatinib and played a role in dasatinib-EGFR degradation. C-cbl activation was induced by ER stress and shown to mediate ER-stress induced EGFR degradation. In addition, AMPK activation was induced by dasatinib, which was proved to be involved in dasatinib-induced ER stress and EGFR degradation. Activation of AMPK with metformin not only enhanced dasatinib-induced growth inhibition and apoptosis but also sensitized dasatinib-resistant cells. Furthermore, xenograft model showed that metformin potentiated anti-cancer effect of dasatinib through activation of AMPK and ER stress. Our results disclose that AMPK-dependent ER stress plays a crucial role in the anti-cancer effect of dasatinib in HNSCC and further activation of AMPK by metformin might enhance dasatinib efficacy. Citation Format: Yu-Chin Lin Lin, Meng-Hsuan Wu, Tzu-Tang Wei, Yun-Chieh Lin, Ching-Chow Chen. AMPK activation mediates dasatinib-induced EGFR degradation and apoptosis in head and neck cancer. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A73. doi:10.1158/1538-7445.CHTME14-A73

The mechanisms of action of metformin on head and neck cancer in the pre-clinical setting: a scoping review

“…Dasatinib, a kinase inhibitor used for the treatment of chronic myeloid leukemia, activates AMPK by reducing ATP through the inactivation of ERK. The activation of AMPK by metformin goes on to induce endoplasmic reticulum stress which degrades EGFR through the c-Cbl lysosome pathway, resulting in apoptosis ( 58 ) ( Figure 2 ). With both dasatinib and metformin activating AMPK, synergistically they reduce cell viability, increase apoptosis in vitro and reduce tumor volume in a HNSCC xenograft model ( 58 ).…”