title: Combined EGFR/MEK Inhibition Prevents the Emergence of Resistance in EGFR-Mutant Lung Cancer.
abstract: Irreversible pyrimidine-based EGFR inhibitors, including WZ4002, selectively inhibit both EGFR-activating and EGFR inhibitor-resistant T790M mutations more potently than wild-type EGFR. Although this class of mutant-selective EGFR inhibitors is effective clinically in lung cancer patients harboring EGFR(T790M), prior preclinical studies demonstrate that acquired resistance can occur through genomic alterations that activate ERK1/2 signaling. Here, we find that ERK1/2 reactivation occurs rapidly following WZ4002 treatment. Concomitant inhibition of ERK1/2 by the MEK inhibitor trametinib prevents ERK1/2 reactivation, enhances WZ4002-induced apoptosis, and inhibits the emergence of resistance in WZ4002-sensitive models known to acquire resistance via both T790M-dependent and T790M-independent mechanisms. Resistance to WZ4002 in combination with trametinib eventually emerges due to AKT/mTOR reactivation. These data suggest that initial cotargeting of EGFR and MEK could significantly impede the development of acquired resistance in EGFR-mutant lung cancer.
  
  
  CONCLUSIONS
  Patients with EGFR-mutant lung cancer develop acquired resistance to EGFR and mutant-selective EGFR tyrosine kinase inhibitors. Here, we show that cotargeting EGFR and MEK can prevent the emergence of a broad variety of drug resistance mechanisms in vitro and in vivo and may be a superior therapeutic regimen for these patients.
authors.affiliation: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Tricker
authors.affiliation: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, 10065, USA.|Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, New York, 10065, USA.
authors.forename: Sharmeen
authors.initials: S
authors.lastname: Uddin
authors.affiliation: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.
authors.forename: Marzia
authors.initials: M
authors.lastname: Capelletti
authors.affiliation: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.
authors.forename: Dalia
authors.initials: D
authors.lastname: Ercan
authors.affiliation: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Ogino
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, 10065, USA.|Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, New York, 10065, USA.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Pratilas
authors.affiliation: Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, New York, 10065, USA.|Department of Medicine, Memorial Sloane Kettering Cancer Center, New York, New York, 10065, USA.
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.|Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.affiliation: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.|Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.|Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, 20115, USA.
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.affiliation: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.|Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.|Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, 20115, USA.
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors; D019893:Ribosomal Protein S6 Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases