Hepatocyte growth factor reduces sensitivity to the epidermal growth factor receptor-tyrosine kinase inhibitor, gefitinib, in lung adenocarcinoma cells harboring wild-type EGFR.

Abstract

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy is an option for lung cancers harboring wild-type EGFR when chemotherapeutic reagents have failed. In this study, we found that the EGFR-TKI, gefitinib, modestly suppressed proliferation of the lung cancer cell lines, A549 and H358, which both harbor wild-type EGFR. Treatment with hepatocyte growth factor (HGF) reduced the sensitivity to gefitinib, whereas sensitivity was restored by treatment with an HGF antibody, a MET inhibitor, or depletion of MET but not ErbB3 gene. Moreover, both PI3K/mTOR inhibitors and MEK inhibitors suppressed proliferation of A549 cells, whereas only PI3K/mTOR inhibitors effectively suppressed cell viability of EGFR mutant PC-9 cells. Our findings suggest that HGF reduced the gefitinib sensitivity through MET and downstream PI3K and MAPK pathways. Combined use of EGFR-TKI and MET inhibitors or inhibition of downstream signaling molecules might be a better second or third line choice for a group of patients with advanced lung cancer harboring wild-type EGFR.

• Authors: Hua Yang, Rong Wang, Shunli Peng, Longhua Chen, Qi Li, Wei Wang
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 13 Pg. 16273-81 (Mar 29 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 26919104 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• HGF protein, human
• Protein Kinase Inhibitors
• Quinazolines
• Hepatocyte Growth Factor
• ErbB Receptors
• Proto-Oncogene Proteins c-met
• Gefitinib

Topics

• Adenocarcinoma (genetics, metabolism, pathology)
• Adenocarcinoma of Lung
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (drug effects, physiology)
• ErbB Receptors (antagonists & inhibitors)
• Gefitinib
• Hepatocyte Growth Factor (metabolism, pharmacology)
• Humans
• Lung Neoplasms (genetics, metabolism, pathology)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-met (antagonists & inhibitors)
• Quinazolines (pharmacology)