Supplementary Figure 5 from 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

doi:10.1158/0008-5472.22391502.v1

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Supplementary Figure 5 from Tankyrase and the Canonical Wnt Pathway Protect Lung Cancer Cells from EGFR Inhibition

journal contribution

posted on 2023-03-30, 21:00 authored by 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

PDF file - 222K, Demonstration that beta-catenin or TCF-4 knockdown results in enhanced sensitivity of NSCLC cells to gefitinib treatment, that beta-catenin or TCF-4 knockdowns reduce the expression of the corresponding protein, that there is minimal correlation between the expression of canonical Wnt target genes and gefitinib sensitivity for a panel of NSCLC cell lines, that there is no significant correlation of SLuGs with gefitinib induced genes, and that SLuGs are not enriched in lung cancer specific genes

History

ARTICLE 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. Cancer Res; 72(16); 4154–64. ©2012 AACR.