Ibrutinib selectively and irreversibly targets EGFR (L858R, Del19) mutant but is moderately resistant to EGFR (T790M) mutant NSCLC Cells
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Hong Wu1,2,*, Aoli Wang1,2,*, Wei Zhang3,*, Beilei Wang1,*, Cheng Chen1,*, Wenchao Wang1, Chen Hu1, Zi Ye4, Zheng Zhao1, Li Wang1, Xixiang Li1, Kailin Yu1, Juan Liu1, Jiaxin Wu1,2, Xiao-E Yan5, Peng Zhao5, Jinhua Wang6, Chu Wang4, Ellen L. Weisberg7, Nathanael S. Gray6, Cai-Hong Yun5, Jing Liu1, Liang Chen3, Qingsong Liu1,2,8
1High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China
2University of Science and Technology of China, Hefei 230036, Anhui, P. R. China
3Collaborative Innovation Center of Cancer Medicine, National Institute of Biological Sciences, Beijing, Beijing 102206, P.R. China
4Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, P.R. China
5Institute of Systems Biomedicine, Department of Biophysics, Beijing Key Laboratory of Tumor Systems Biology and Center for Molecular and Translational Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, P.R. China
6Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
7Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
8Hefei Science Center, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China
*These authors have contributed equally to this work
Jing Liu, e-mail: firstname.lastname@example.org
Liang Chen, e-mail: email@example.com
Qingsong Liu, e-mail: firstname.lastname@example.org
Keywords: ibrutinib, NSCLC, EGFR mutation, drug resistance, drug combination
Received: June 24, 2015 Accepted: August 24, 2015 Published: September 05, 2015
Through comprehensive comparison study, we found that ibrutinib, a clinically approved covalent BTK kinase inhibitor, was highly active against EGFR (L858R, del19) mutant driven NSCLC cells, but moderately active to the T790M ‘gatekeeper’ mutant cells and not active to wild-type EGFR NSCLC cells. Ibrutinib strongly affected EGFR mediated signaling pathways and induced apoptosis and cell cycle arrest (G0/G1) in mutant EGFR but not wt EGFR cells. However, ibrutinib only slowed down tumor progression in PC-9 and H1975 xenograft models. MEK kinase inhibitor, GSK1120212, could potentiate ibrutinib’s effect against the EGFR (L858R/T790M) mutation in vitro but not in vivo. These results suggest that special drug administration might be required to achieve best clinical response in the ongoing phase I/II clinical trial with ibrutinib for NSCLC.
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