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.