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?-catenin contributes to lung tumor development induced by EGFR mutations.

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 ?-catenin is essential for development of EGFR-mutated lung cancers. ?-Catenin was upregulated and activated in EGFR-mutated cells. Mutant EGFR preferentially bound to and tyrosine phosphorylated ?-catenin, leading to an increase in ?-catenin-mediated transactivation, particularly in cells harboring the gefitinib/erlotinib-resistant gatekeeper EGFR-T790M mutation. Pharmacologic inhibition of ?-catenin suppressed EGFR-L858R-T790M mutated lung tumor growth, and genetic deletion of the ?-catenin gene dramatically reduced lung tumor formation in EGFR-L858R-T790M transgenic mice. These data suggest that ?-catenin plays an essential role in lung tumorigenesis and that targeting the ?-catenin pathway may provide novel strategies to prevent lung cancer development or overcome resistance to EGFR TKIs.

SUBMITTER: Nakayama S

PROVIDER: S-EPMC4199914 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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β-catenin contributes to lung tumor development induced by EGFR mutations.

Nakayama Sohei S Sng Natasha N Carretero Julian J Welner Robert R Hayashi Yuichiro Y Yamamoto Mihoko M Tan Alistair J AJ Yamaguchi Norihiro N Yasuda Hiroyuki H Li Danan D Soejima Kenzo K Soo Ross A RA Costa Daniel B DB Wong Kwok-Kin KK Kobayashi Susumu S SS

Cancer research 20140827 20

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 inc ...[more]

PMID: 25164010

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Project description:Epidermal growth factor receptor (EGFR) mutations are present in the majority of patients with non-small cell lung cancer (NSCLC) responsive to the EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib. These EGFR-dependent tumors eventually become TKI resistant, and the common secondary T790M mutation accounts for half the tumors with acquired resistance to gefitinib. However, the key proapoptotic proteins involved in TKI-induced cell death and other secondary mutations involved in resistance remain unclear. The objective of this study was to identify the mechanism of EGFR TKI-induced apoptosis and secondary resistant mutations that affect this process.To study TKI-induced cell death and mechanisms of resistance, we used lung cancer cell lines (with or without EGFR mutations), Ba/F3 cells stably transfected with EGFR mutation constructs, and tumor samples from a gefitinib-resistant patient. Here we show that up-regulation of the BH3-only polypeptide BIM (also known as BCL2-like 11) correlated with gefitinib-induced apoptosis in gefitinib-sensitive EGFR-mutant lung cancer cells. The T790M mutation blocked gefitinib-induced up-regulation of BIM and apoptosis. This blockade was overcome by the irreversible TKI CL-387,785. Knockdown of BIM by small interfering RNA was able to attenuate apoptosis induced by EGFR TKIs. Furthermore, from a gefitinib-resistant patient carrying the activating L858R mutation, we identified a novel secondary resistant mutation, L747S in cis to the activating mutation, which attenuated the up-regulation of BIM and reduced apoptosis.Our results provide evidence that BIM is involved in TKI-induced apoptosis in sensitive EGFR-mutant cells and that both attenuation of the up-regulation of BIM and resistance to gefitinib-induced apoptosis are seen in models that contain the common EGFR T790M and the novel L747S secondary resistance mutations. These findings also suggest that induction of BIM may have a role in the treatment of TKI-resistant tumors.

Dataset Information

?-catenin contributes to lung tumor development induced by EGFR mutations.

Publications

β-catenin contributes to lung tumor development induced by EGFR mutations.

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