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

Abstract

Lung cancer is the leading cause of death worldwide. Adenocarcinomas, the most common histological 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 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.

Loss of PKCδ Induces Prostate Cancer Resistance to Paclitaxel through Activation of Wnt/β-Catenin Pathway and Mcl-1 Accumulation

“…These inhibitors used in combined therapy with paclitaxel resulted in an increased apoptotic response in comparison with single inhibitor or paclitaxel treatment, even in PKCd-silenced cells. Supporting our results, other authors showed that the inhibition of these pathways improved the apoptotic response to EGFR-targeting therapy in lung cancer (28), deguelin and microtubule-targeting drugs in prostate cancer (29,31), paclitaxel and irinotecan in colon cancer (30), or tamoxifen in glioma cells (24).…”

“…On the basis of these articles, we propose that PKCd would modulate Mcl-1 by regulation of the Wnt/b-catenin pathway in prostate cancer cells. The Wnt/b-catenin pathway regulates embryogenesis, proliferation, cell differentiation, or migration, and it is abnormally activated in different tumor types (18,20,23,24,28,29). b-catenin is a strongly regulated factor with a central role in this pathway.…”

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

“…Indeed, a combination of an EGFR and Tankyrase inhibition recently revealed a close functional correlation of both pathways and confirmed the synergistic effect of a dual antagonistic treatment in lung cancer cells [477]. Zibotentan, a ET(A)R antagonist when combined with the EGFR inhibitor gefitinib, reduces -catenin activity [387].…”

Lgr4 Promotes Glioma Cell Proliferation through Activation of Wnt Signaling

“…The common hallmark in various human caner tissues is the nuclear retention of β-catenin, the main effector of the canonical Wnt signaling pathway (Fodde et al, 2001;Casás-Selves et al, 2012). In the absence of Wnt ligands, β-catenin is tightly regulated by a multi-protein complex including: the tumour suppressor APC, the scaffolding protein axin, and the phosphokinases GSK-3β and CK1 (Fodde et al, 2001;Casás-Selves et al, 2012).…”

“…In the absence of Wnt ligands, β-catenin is tightly regulated by a multi-protein complex including: the tumour suppressor APC, the scaffolding protein axin, and the phosphokinases GSK-3β and CK1 (Fodde et al, 2001;Casás-Selves et al, 2012). Upon ligand activation, the complex is destabilized, allowing for cytoplasmic β-catenin accumulation with subsequent nuclear translocation (Fodde et al, 2001;Moon et al, 2004).…”