1. Tankyrase and the canonical Wnt pathway protect lung cancer cells from EGFR inhibition.
- Author
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Casás-Selves M, Kim J, Zhang Z, Helfrich BA, Gao D, Porter CC, Scarborough HA, Bunn PA Jr, Chan DC, Tan AC, and DeGregori J
- Subjects
- Adenocarcinoma, Bronchiolo-Alveolar drug therapy, Adenocarcinoma, Bronchiolo-Alveolar enzymology, Adenocarcinoma, Bronchiolo-Alveolar genetics, Adenocarcinoma, Bronchiolo-Alveolar metabolism, Animals, Antineoplastic Agents pharmacology, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung enzymology, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung metabolism, Cell Line, Tumor, ErbB Receptors metabolism, Female, Gefitinib, Humans, Lung Neoplasms enzymology, Lung Neoplasms genetics, Mice, Mice, Nude, Quinazolines pharmacology, RNA, Small Interfering administration & dosage, RNA, Small Interfering genetics, Signal Transduction, Xenograft Model Antitumor Assays, ErbB Receptors antagonists & inhibitors, Lung Neoplasms drug therapy, Lung Neoplasms metabolism, Protein Kinase Inhibitors pharmacology, Tankyrases metabolism, Wnt Proteins metabolism
- Abstract
Lung cancer is the leading cause of death worldwide. Adenocarcinomas, the most common histologic subtype of non-small cell lung cancer (NSCLC), are frequently associated with activating mutations in the epidermal growth factor receptor (EGFR) gene. Although these patients often respond clinically to the EGFR tyrosine kinase inhibitors erlotinib and gefitinib, relapse inevitably occurs, suggesting the development of escape mechanisms that promote cell survival. Using a loss-of-function, whole genome short hairpin RNA (shRNA) screen, we identified that the canonical Wnt pathway contributes to the maintenance of NSCLC cells during EGFR inhibition, particularly the poly-ADP-ribosylating enzymes tankyrase 1 and 2 that positively regulate canonical Wnt signaling. Inhibition of tankyrase and various other components of the Wnt pathway with shRNAs or small molecules significantly increased the efficacy of EGFR inhibitors both in vitro and in vivo. Our findings therefore reveal a critical role for tankyrase and the canonical Wnt pathway in maintaining lung cancer cells during EGFR inhibition. Targeting the Wnt-tankyrase-β-catenin pathway together with EGFR inhibition may improve clinical outcome in patients with NSCLC., (©2012 AACR.)
- Published
- 2012
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