2. Academic Validation
  3. Ibrutinib selectively and irreversibly targets EGFR (L858R, Del19) mutant but is moderately resistant to EGFR (T790M) mutant NSCLC Cells

Ibrutinib selectively and irreversibly targets EGFR (L858R, Del19) mutant but is moderately resistant to EGFR (T790M) mutant NSCLC Cells

  • Oncotarget. 2015 Oct 13;6(31):31313-22. doi: 10.18632/oncotarget.5182.
Hong Wu 1 2,  Aoli Wang 1 2,  Wei Zhang 3,  Beilei Wang 1,  Cheng Chen 1,  Wenchao Wang 1,  Chen Hu 1,  Zi Ye 4,  Zheng Zhao 1,  Li Wang 1,  Xixiang Li 1,  Kailin Yu 1,  Juan Liu 1,  Jiaxin Wu 1 2,  Xiao-E Yan 5,  Peng Zhao 5,  Jinhua Wang 6,  Chu Wang 4,  Ellen L Weisberg 7,  Nathanael S Gray 6,  Cai-Hong Yun 5,  Jing Liu 1,  Liang Chen 3,  Qingsong Liu 1 2 8
Affiliations

Affiliations

  • 1 High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.
  • 2 University of Science and Technology of China, Hefei 230036, Anhui, P. R. China.
  • 3 Collaborative Innovation Center of Cancer Medicine, National Institute of Biological Sciences, Beijing, Beijing 102206, P.R. China.
  • 4 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.
  • 5 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.
  • 6 Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
  • 7 Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
  • 8 Hefei Science Center, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.
PMID: 26375053 DOI: 10.18632/oncotarget.5182
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.

Keywords

EGFR mutation; NSCLC; drug combination; drug resistance; ibrutinib.

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