Guiqin Xie1,2, Ailin Zhu1, Xinbin Gu1,2. 1. Department of Oral Pathology, Howard University College of Dentistry, Washington, DC, USA. 2. Department of Cancer Center, Howard University College of Dentistry, Washington, DC, USA.
Abstract
BACKGROUND: Epidermal growth factor receptor (EGFR) overexpression is one of the most notable characteristics in head and neck squamous cell carcinoma (HNSCC). The MAPK kinase (MEK) inhibitor trametinib has shown efficacy to treat HNSCC; however, the molecular mechanism remains unclear. METHODS: HNSCC lines, mouse models, Western blot, and flow cytometry were employed to analyze the anticancer effects of trametinib. RESULTS: The JHU-011, JHU-022, and JHU-029 HNSCC cells with different genetic alterations were highly susceptible to trametinib. Trametinib effectively reduced EGFR expression, which was accompanied by the reduction of pro-survival protein MYC, and the increased expression of a MYC-targeted cyclin-dependent kinase inhibitor p27kip1 and pro-apoptotic protein BIM. Trametinib resulted in G1 arrest of the cells, markedly reduced cell numbers in S phase, and significantly increased apoptosis. In mouse models, trametinib strongly inhibited tumors growth. CONCLUSIONS: The MAPK-ERK signaling inhibition by trametinib may target EGFR and the downstream proteins against HNSCC.
BACKGROUND: Epidermal growth factor receptor (EGFR) overexpression is one of the most notable characteristics in head and neck squamous cell carcinoma (HNSCC). The MAPK kinase (MEK) inhibitor trametinib has shown efficacy to treat HNSCC; however, the molecular mechanism remains unclear. METHODS: HNSCC lines, mouse models, Western blot, and flow cytometry were employed to analyze the anticancer effects of trametinib. RESULTS: The JHU-011, JHU-022, and JHU-029 HNSCC cells with different genetic alterations were highly susceptible to trametinib. Trametinib effectively reduced EGFR expression, which was accompanied by the reduction of pro-survival protein MYC, and the increased expression of a MYC-targeted cyclin-dependent kinase inhibitor p27kip1 and pro-apoptotic protein BIM. Trametinib resulted in G1 arrest of the cells, markedly reduced cell numbers in S phase, and significantly increased apoptosis. In mouse models, trametinib strongly inhibited tumors growth. CONCLUSIONS: The MAPK-ERK signaling inhibition by trametinib may target EGFR and the downstream proteins against HNSCC.
Authors: Tikvah K Hayes; Nicole F Neel; Chaoxin Hu; Prson Gautam; Melissa Chenard; Brian Long; Meraj Aziz; Michelle Kassner; Kirsten L Bryant; Mariaelena Pierobon; Raoud Marayati; Swapnil Kher; Samuel D George; Mai Xu; Andrea Wang-Gillam; Ahmed A Samatar; Anirban Maitra; Krister Wennerberg; Emanuel F Petricoin; Hongwei H Yin; Barry Nelkin; Adrienne D Cox; Jen Jen Yeh; Channing J Der Journal: Cancer Cell Date: 2015-12-24 Impact factor: 31.743
Authors: Georgina V Long; Axel Hauschild; Mario Santinami; Victoria Atkinson; Mario Mandalà; Vanna Chiarion-Sileni; James Larkin; Marta Nyakas; Caroline Dutriaux; Andrew Haydon; Caroline Robert; Laurent Mortier; Jacob Schachter; Dirk Schadendorf; Thierry Lesimple; Ruth Plummer; Ran Ji; Pingkuan Zhang; Bijoyesh Mookerjee; Jeff Legos; Richard Kefford; Reinhard Dummer; John M Kirkwood Journal: N Engl J Med Date: 2017-09-10 Impact factor: 91.245