title: EGFR and myosin II inhibitors cooperate to suppress EGFR-T790M-mutant NSCLC cells.
abstract: An acquired mutation (T790M) in the epidermal growth factor receptor (EGFR) accounts for half of all relapses in non-small cell lung cancer (NSCLC) patients who initially respond to EGFR kinase inhibitors. In this study, we demonstrated for the first time that EGFR-T790M interacts with the cytoskeletal components, myosin heavy chain 9 (MYH9) and β-actin, in the nucleus of H1975 cells carrying the T790M-mutant EGFR. The interactions of EGFR with MYH9 and β-actin were reduced in the presence of blebbistatin, a specific inhibitor for the MYH9-β-actin interaction, suggesting that the EGFR interaction with MYH9 and β-actin is affected by the integrity of the cytoskeleton. These physical interactions among MYH9, β-actin, and EGFR were also impaired by CL-387,785, a kinase inhibitor for EGFR-T790M. Furthermore, CL-387,785 and blebbistatin interacted in a synergistic fashion to suppress cell proliferation and induce apoptosis in H1975 cells. The combination of CL-387,785 and blebbistatin enhanced the down-regulation of cyclooxygenase-2 (COX-2), a transcriptional target of nuclear EGFR. Overall, our findings demonstrate that disrupting EGFR interactions with the cytoskeletal components enhanced the anti-cancer effects of CL-387,785 against H1975 cells, suggesting a novel therapeutic approach for NSCLC cells that express the drug-resistant EGFR-T790M.
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan, ROC.
authors.forename: Huan-Chih
authors.initials: HC
authors.lastname: Chiu
authors.forename: Teng-Yuan
authors.initials: TY
authors.lastname: Chang
authors.forename: Chin-Ting
authors.initials: CT
authors.lastname: Huang
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Chao
authors.forename: John T-A
authors.initials: JT
authors.lastname: Hsu
mesh_terms: D000199:Actins / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D051546:Cyclooxygenase 2 / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D005434:Flow Cytometry; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006801:Humans; D047468:Immunoprecipitation; D020409:Molecular Motor Proteins / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000378:metabolism*; D024462:Myosin Type II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011485:Protein Binding; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000199:Actins; D006576:Heterocyclic Compounds, 4 or More Rings; C103814:MYH9 protein, human; D020409:Molecular Motor Proteins; D011799:Quinazolines; C472645:blebbistatin; C118029:CL 387785; D051546:Cyclooxygenase 2; C512478:EGFR protein, human; D066246:ErbB Receptors; D024462:Myosin Type II; D018995:Myosin Heavy Chains