Tankyrase and the canonical Wnt pathway protect lung cancer cells from EGFR inhibition

Matias Casás-Selves, Jihye Kim, Zhiyong Zhang, Barbara A. Helfrich, Dexiang Gao, Christopher C. Porter, Hannah A. Scarborough, Paul A. Bunn, Daniel C. Chan, Aik Choon Tan, James DeGregori

Research output: Contribution to journalArticlepeer-review

93 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4154-4164
Number of pages11
JournalCancer Research
Volume72
Issue number16
DOIs
Publication statusPublished - 2012 Aug 15

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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