title: EGFR and HER2 signals play a salvage role in MEK1-mutated gastric cancer after MEK inhibition.
abstract: Since the prognosis of unresectable advanced gastric cancer remains poor, novel therapeutic strategies are needed. Somatic MEK1 gene mutations have been reported as oncogenic activating mutations in gastric cancer, and MEK inhibitors can be effective against such gastric cancers. In the present study, however, activated EGFR and HER2 signals after treatment with a MEK inhibitor (trametinib) were found in a MEK1-mutated gastric cancer cell line (OCUM-1 cell line) using a phospho-receptor tyrosine kinase array. The phosphorylation of EGFR and HER2 reactivated ERK1/2, which had been inhibited by trametinib, and EGF stimulation led to resistance to trametinib in this cell line. Lapatinib, an EGFR and an HER2 inhibitor, reversed the activation of ERK1/2 by inhibiting the phosphorylation of EGFR and HER2 and cancelled the resistance. The combination of trametinib and lapatinib synergistically inhibited the cell growth of the OCUM-1 cell line and strongly induced apoptosis by inhibiting the activated EGFR and HER2 signals. These results suggest that the EGFR and HER2 signals play a salvage role and are related to resistance to MEK inhibitors in MEK1‑mutated gastric cancer. Moreover, combination therapy with trametinib and lapatinib can exhibit a synergistic effect and may contribute to overcoming the resistance to MEK inhibitors.
authors.affiliation: Department of Genome Biology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Takuro
authors.initials: T
authors.lastname: Mizukami
authors.affiliation: Department of Genome Biology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Togashi
authors.affiliation: Department of Genome Biology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Sogabe
authors.affiliation: Department of Genome Biology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Banno
authors.affiliation: Department of Genome Biology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Terashima
authors.affiliation: Department of Genome Biology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Marco A
authors.initials: MA
authors.lastname: De Velasco
authors.affiliation: Department of Genome Biology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Sakai
authors.affiliation: Department of Genome Biology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Fujita
authors.affiliation: Department of Genome Biology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Shuta
authors.initials: S
authors.lastname: Tomida
authors.affiliation: Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
authors.forename: Takako Eguchi
authors.initials: TE
authors.lastname: Nakajima
authors.affiliation: Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
authors.forename: Narikazu
authors.initials: N
authors.lastname: Boku
authors.affiliation: Department of Genome Biology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000077341:Lapatinib; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*
chemical_list: D066246:ErbB Receptors; D000077341:Lapatinib; D048369:MAP Kinase Kinase 1; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C560077:trametinib; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C482125:MAP2K1 protein, human