Abstract:
:The discovery of somatic mutations in EGFR and development of EGFR tyrosine kinase inhibitors (TKI) have revolutionized treatment for lung cancer. However, resistance to TKIs emerges in almost all patients and currently no effective treatment is available. Here, we show that β-catenin is essential for development of EGFR-mutated lung cancers. β-Catenin was upregulated and activated in EGFR-mutated cells. Mutant EGFR preferentially bound to and tyrosine phosphorylated β-catenin, leading to an increase in β-catenin-mediated transactivation, particularly in cells harboring the gefitinib/erlotinib-resistant gatekeeper EGFR-T790M mutation. Pharmacologic inhibition of β-catenin suppressed EGFR-L858R-T790M mutated lung tumor growth, and genetic deletion of the β-catenin gene dramatically reduced lung tumor formation in EGFR-L858R-T790M transgenic mice. These data suggest that β-catenin plays an essential role in lung tumorigenesis and that targeting the β-catenin pathway may provide novel strategies to prevent lung cancer development or overcome resistance to EGFR TKIs.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Nakayama S,Sng N,Carretero J,Welner R,Hayashi Y,Yamamoto M,Tan AJ,Yamaguchi N,Yasuda H,Li D,Soejima K,Soo RA,Costa DB,Wong KK,Kobayashi SSdoi
10.1158/0008-5472.CAN-14-0184subject
Has Abstractpub_date
2014-10-15 00:00:00pages
5891-902issue
20eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-14-0184journal_volume
74pub_type
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