Hepatocyte growth factor reduces susceptibility to an irreversible epidermal growth factor receptor inhibitor in EGFR-T790M mutant lung cancer.

Abstract

PURPOSE:

The secondary T790M mutation in epidermal growth factor receptor (EGFR) is the most frequent cause of acquired resistance to the reversible EGFR tyrosine kinase inhibitors (EGFR-TKI), gefitinib and erlotinib, in lung cancer. Irreversible EGFR-TKIs are expected to overcome the reversible EGFR-TKI resistance of lung cancer harboring T790M mutation in EGFR. However, it is clear that resistance may also develop to this class of inhibitors. We showed previously that hepatocyte growth factor (HGF) induced gefitinib resistance of lung cancer harboring EGFR-activating mutations. Here, we investigated whether HGF induced resistance to the irreversible EGFR-TKI, CL-387,785, in lung cancer cells (H1975) harboring both L858R activating mutation and T790M secondary mutation in EGFR.

EXPERIMENTAL DESIGN:

CL-387,785 sensitivity and signal transduction in H1975 cells were examined in the presence or absence of HGF or HGF-producing fibroblasts with or without HGF-MET inhibitors.

RESULTS:

HGF reduced susceptibility to CL-387,785 in H1975 cells. Western blotting and small interfering RNA analyses indicated that HGF-induced hyposensitivity was mediated by the MET/phosphoinositide 3-kinase/Akt signaling pathway independent of EGFR, ErbB2, ErbB3, and ErbB4. Hyposensitivity of H1975 cells to CL-387,785 was also induced by coculture with high-level HGF-producing lung fibroblasts. The hyposensitivity was abrogated by treatment with anti-HGF neutralizing antibody, HGF antagonist NK4, or MET-TKI.

CONCLUSIONS:

We showed HGF-mediated hyposensitivity as a novel mechanism of resistance to irreversible EGFR-TKIs. It will be clinically valuable to investigate the involvement of HGF-MET-mediated signaling in de novo and acquired resistance to irreversible EGFR-TKIs in lung cancer harboring T790M mutation in EGFR.

• Authors: Tadaaki Yamada, Kunio Matsumoto, Wei Wang, Qi Li, Yasuhiko Nishioka, Yoshitaka Sekido, Saburo Sone, Seiji Yano
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 16 Issue 1 Pg. 174-83 (Jan 01 2010) ISSN: 1557-3265 [Electronic] United States
• PMID: 20008840 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Kinase Inhibitors
• Receptors, Growth Factor
• Hepatocyte Growth Factor
• ErbB Receptors
• MET protein, human
• Protein-Tyrosine Kinases
• Proto-Oncogene Proteins c-met
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinase 3

Topics

• Adenocarcinoma (drug therapy, genetics)
• Drug Resistance, Neoplasm
• ErbB Receptors (antagonists & inhibitors, genetics)
• Fibroblasts (metabolism)
• Hepatocyte Growth Factor (pharmacology)
• Humans
• Lung Neoplasms (drug therapy, genetics)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Mutation
• Protein Kinase Inhibitors (therapeutic use)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins c-met (metabolism)
• Receptors, Growth Factor (metabolism)
• Signal Transduction