Multiple receptor tyrosine kinase activation attenuates therapeutic efficacy of the fibroblast growth factor receptor 2 inhibitor AZD4547 in FGFR2 amplified gastric cancer.

Abstract

Fibroblast growth factor receptor 2 (FGFR2)-targeted therapy has attracted considerable attention as novel anticancer agents in gastric cancer (GC). However, intrinsic or acquired drug resistance has emerged as a major challenge to their clinical use. In this study, we demonstrated that several receptor tyrosine kinase (RTK), including EGFR, HER3 and MET, activations contributed to AZD4547 (a selective FGFR2 inhibitor) hyposensitivity in FGFR2 amplified GC cells. The rescue effect was abrogated by inhibiting these RTKs with their targeted tyrosine kinase inhibitors (TKIs). In addition, synergy in growth inhibition was observed when the GC cells were treated with a combination of AZD4547 and cetuximab (an EGFR monoclonal antibody) both in vitro and in vivo. More importantly, tissue microarray analysis revealed that these resistance-conferring RTKs were highly expressed in FGFR2 positive GC patients. Taken together, these observations demonstrated RTKs including EGFR, HER3 and MET activations as novel mechanisms of hyposensitivity to AZD4547. It will be clinically valuable to investigate the involvement of RTK-mediated signaling in intrinsicor acquired resistance to FGFR2 TKIs in GC. A combination targeted therapeutic strategy may be recommended for treating FGFR2 amplified GC patients with these RTK activations.

• Authors: Jinjia Chang, Shanshan Wang, Zhe Zhang, Xinyang Liu, Zheng Wu, Ruixuan Geng, Xiaoxiao Ge, Congqi Dai, Rujiao Liu, Qunling Zhang, Wenhua Li, Jin Li
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 4 Pg. 2009-22 (Feb 10 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25576915 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AZD4547
• Antineoplastic Agents
• Benzamides
• Piperazines
• Pyrazoles
• Receptor Protein-Tyrosine Kinases
• Receptor, Fibroblast Growth Factor, Type 2
• Cetuximab

Topics

• Adult
• Aged
• Aged, 80 and over
• Animals
• Antineoplastic Agents (pharmacology)
• Benzamides (pharmacology)
• Blotting, Western
• Breast Neoplasms (drug therapy, genetics, metabolism)
• Cell Line, Tumor
• Cell Survival (drug effects, genetics)
• Cetuximab (pharmacology)
• Drug Synergism
• Enzyme Activation (drug effects)
• Female
• Gene Amplification
• Humans
• In Situ Hybridization, Fluorescence
• MAP Kinase Signaling System (drug effects)
• Male
• Mice, Nude
• Middle Aged
• Piperazines (pharmacology)
• Pyrazoles (pharmacology)
• Receptor Protein-Tyrosine Kinases (metabolism)
• Receptor, Fibroblast Growth Factor, Type 2 (antagonists & inhibitors, genetics, metabolism)
• Stomach Neoplasms (drug therapy, genetics, metabolism)
• Xenograft Model Antitumor Assays