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: Takuro Mizukami, Yosuke Togashi, Shunsuke Sogabe, Eri Banno, Masato Terashima, Marco A De Velasco, Kazuko Sakai, Yoshihiko Fujita, Shuta Tomida, Takako Eguchi Nakajima, Narikazu Boku, Kazuto Nishio
• Journal: International journal of oncology (Int J Oncol) Vol. 47 Issue 2 Pg. 499-505 (Aug 2015) ISSN: 1791-2423 [Electronic] Greece
• PMID: 26081723 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Kinase Inhibitors
• Pyridones
• Pyrimidinones
• Quinazolines
• Lapatinib
• trametinib
• EGFR protein, human
• ERBB2 protein, human
• ErbB Receptors
• Receptor, ErbB-2
• MAP Kinase Kinase 1
• MAP2K1 protein, human

Topics

• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Drug Synergism
• ErbB Receptors (genetics, metabolism)
• Humans
• Lapatinib
• MAP Kinase Kinase 1 (antagonists & inhibitors, genetics)
• MAP Kinase Signaling System (drug effects)
• Mutation
• Phosphorylation (drug effects)
• Protein Kinase Inhibitors (pharmacology)
• Pyridones (pharmacology)
• Pyrimidinones (pharmacology)
• Quinazolines (pharmacology)
• Receptor, ErbB-2 (genetics, metabolism)
• Stomach Neoplasms (drug therapy, genetics, metabolism)