title: Ibrutinib selectively and irreversibly targets EGFR (L858R, Del19) mutant but is moderately resistant to EGFR (T790M) mutant NSCLC Cells.
abstract: 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.
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|University of Science and Technology of China, Hefei 230036, Anhui, P. R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|University of Science and Technology of China, Hefei 230036, Anhui, P. R. China.
authors.forename: Aoli
authors.initials: A
authors.lastname: Wang
authors.affiliation: Collaborative Innovation Center of Cancer Medicine, National Institute of Biological Sciences, Beijing, Beijing 102206, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.
authors.forename: Beilei
authors.initials: B
authors.lastname: Wang
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Chen
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.
authors.forename: Wenchao
authors.initials: W
authors.lastname: Wang
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.
authors.forename: Chen
authors.initials: C
authors.lastname: Hu
authors.affiliation: Synthetic 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.
authors.forename: Zi
authors.initials: Z
authors.lastname: Ye
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.
authors.forename: Xixiang
authors.initials: X
authors.lastname: Li
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.
authors.forename: Kailin
authors.initials: K
authors.lastname: Yu
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|University of Science and Technology of China, Hefei 230036, Anhui, P. R. China.
authors.forename: Jiaxin
authors.initials: J
authors.lastname: Wu
authors.affiliation: Institute 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.
authors.forename: Xiao-E
authors.initials: XE
authors.lastname: Yan
authors.affiliation: Institute 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.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhao
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wang
authors.affiliation: Synthetic 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.
authors.forename: Chu
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Weisberg
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.affiliation: Institute 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.
authors.forename: Cai-Hong
authors.initials: CH
authors.lastname: Yun
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Collaborative Innovation Center of Cancer Medicine, National Institute of Biological Sciences, Beijing, Beijing 102206, P.R. China.
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|University of Science and Technology of China, Hefei 230036, Anhui, P. R. China.|Hefei Science Center, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Liu
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002453:Cell Cycle; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics*; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; C512478:EGFR protein, human; D066246:ErbB Receptors; D000225:Adenine
keywords: EGFR mutation; NSCLC; drug combination; drug resistance; ibrutinib