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 journalArticle

84 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
Externally publishedYes

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Tankyrases
Wnt Signaling Pathway
Epidermal Growth Factor Receptor
Lung Neoplasms
Non-Small Cell Lung Carcinoma
erbB-1 Genes
Catenins
Protein-Tyrosine Kinases
Adenosine Diphosphate
Small Interfering RNA
Cause of Death
Cell Survival
Adenocarcinoma
Maintenance
Genome
Recurrence
Mutation
Enzymes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Casás-Selves, M., Kim, J., Zhang, Z., Helfrich, B. A., Gao, D., Porter, C. C., ... DeGregori, J. (2012). Tankyrase and the canonical Wnt pathway protect lung cancer cells from EGFR inhibition. Cancer Research, 72(16), 4154-4164. https://doi.org/10.1158/0008-5472.CAN-11-2848

Tankyrase and the canonical Wnt pathway protect lung cancer cells from EGFR inhibition. / Casás-Selves, Matias; Kim, Jihye; Zhang, Zhiyong; Helfrich, Barbara A.; Gao, Dexiang; Porter, Christopher C.; Scarborough, Hannah A.; Bunn, Paul A.; Chan, Daniel C.; Tan, Aik-Choon; DeGregori, James.

In: Cancer Research, Vol. 72, No. 16, 15.08.2012, p. 4154-4164.

Research output: Contribution to journalArticle

Casás-Selves, M, Kim, J, Zhang, Z, Helfrich, BA, Gao, D, Porter, CC, Scarborough, HA, Bunn, PA, Chan, DC, Tan, A-C & DeGregori, J 2012, 'Tankyrase and the canonical Wnt pathway protect lung cancer cells from EGFR inhibition', Cancer Research, vol. 72, no. 16, pp. 4154-4164. https://doi.org/10.1158/0008-5472.CAN-11-2848
Casás-Selves M, Kim J, Zhang Z, Helfrich BA, Gao D, Porter CC et al. Tankyrase and the canonical Wnt pathway protect lung cancer cells from EGFR inhibition. Cancer Research. 2012 Aug 15;72(16):4154-4164. https://doi.org/10.1158/0008-5472.CAN-11-2848
Casás-Selves, Matias ; Kim, Jihye ; Zhang, Zhiyong ; Helfrich, Barbara A. ; Gao, Dexiang ; Porter, Christopher C. ; Scarborough, Hannah A. ; Bunn, Paul A. ; Chan, Daniel C. ; Tan, Aik-Choon ; DeGregori, James. / Tankyrase and the canonical Wnt pathway protect lung cancer cells from EGFR inhibition. In: Cancer Research. 2012 ; Vol. 72, No. 16. pp. 4154-4164.
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