Tankyrase and the canonical Wnt pathway protect lung cancer cells from EGFR inhibition.
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.
Department of Biochemistry and Molecular Genetics, Program in Molecular Biology, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
Matias
M
Casás-Selves
Jihye
J
Kim
Zhiyong
Z
Zhang
Barbara A
BA
Helfrich
Dexiang
D
Gao
Christopher C
CC
Porter
Hannah A
HA
Scarborough
Paul A
PA
Bunn
Daniel C
DC
Chan
Aik Choon
AC
Tan
James
J
DeGregori
D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D015398:Signal Transduction; D038501:Tankyrases / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000077156:Gefitinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D034741:RNA, Small Interfering; D038501:Tankyrases; D051153:Wnt Proteins; C418109:TNKS protein, human