Activation of HER family members in gastric carcinoma cells mediates resistance to MET inhibition

Molecular Cancer

Research

Cristina Migliore¹  Simona Corso¹  Silvia Giordano¹  Andrea Bertotti¹  Elena Ghiso¹  Livio Trusolino¹  Paolo M Comoglio¹  Virna Cepero²  J Rafael Sierra² 

[1] Institute for Cancer Research and Treatment, University of Torino Medical School, Candiolo (Torino), Italy;Institute for Cancer Research and Treatment, University of Torino Medical School, Candiolo (Torino), Italy;University Health Network, Ontario Cancer Institute and Princess Margaret Hospital, M5G 2M9, Toronto, ON, Canada;

关键词: Gastric Cancer;    Epidermal Growth Factor;    Gefitinib;    Gastric Cancer Cell;    Gastric Cancer Cell Line;   

DOI  :  10.1186/1476-4598-9-121

 received in 2009-12-15, accepted in 2010-05-26,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundGastric cancer is the second leading cause of cancer mortality in the world. The receptor tyrosine kinase MET is constitutively activated in many gastric cancers and its expression is strictly required for survival of some gastric cancer cells. Thus, MET is considered a good candidate for targeted therapeutic intervention in this type of tumor, and MET inhibitors recently entered clinical trials. One of the major problems of therapies targeting tyrosine kinases is that many tumors are not responsive to treatment or eventually develop resistance to the drugs. Perspective studies are thus mandatory to identify the molecular mechanisms that could cause resistance to these therapies.ResultsOur in vitro and in vivo results demonstrate that, in MET-addicted gastric cancer cells, the activation of HER (Human Epidermal Receptor) family members induces resistance to MET silencing or inhibition by PHA-665752 (a selective kinase inhibitor). We provide molecular evidences highlighting the role of EGFR, HER3, and downstream signaling pathways common to MET and HER family in resistance to MET inhibitors. Moreover, we show that an in vitro generated gastric cancer cell line resistant to MET-inhibition displays overexpression of HER family members, whose activation contributes to maintenance of resistance.ConclusionsOur findings predict that gastric cancer tumors bearing constitutive activation of HER family members are poorly responsive to MET inhibition, even if this receptor is constitutively active. Moreover, the appearance of these alterations might also be responsible for the onset of resistance in initially responsive tumors.

【 授权许可】

CC BY   
© Corso et al; licensee BioMed Central Ltd. 2010