Wnt/β-catenin alterations are prominent in human malignancies. In non-small cell lung
cancer (NSCLC), β-catenin and APC mutations are uncommon, but Wnt signaling is important
in NSCLC cell lines, and Wnt inhibition reduces proliferation. Overexpression of Wnt-1,
-2, -3, and -5a and of Wnt-pathway components Frizzled-8, Dishevelled, Porcupine,
and TCF-4 is common in resected NSCLC and is associated with poor prognosis. Conversely,
noncanonical Wnt-7a suppresses NSCLC development and is often downregulated. Although
β-catenin is often expressed in NSCLCs, it was paradoxically associated with improved
prognosis in some series, possibly because of E-cadherin interactions. Downregulation
of Wnt inhibitors (eg, by hypermethylation) is common in NSCLC tumor cell lines and
resected samples; may be associated with high stage, dedifferentiation, and poor prognosis;
and has been reported for AXIN, sFRPs 1-5, WIF-1, Dkk-1, Dkk-3, HDPR1, RUNX3, APC,
CDX2, DACT2, TMEM88, Chibby, NKD1, EMX2, ING4, and miR-487b. AXIN is also destabilized
by tankyrases, and GSK3β may be inactivated through phosphorylation by EGFR. Preclinically,
restoration of Wnt inhibitor function is associated with reduced Wnt signaling, decreased
cell proliferation, and increased apoptosis. Wnt signaling may also augment resistance
to cisplatin, docetaxel, and radiotherapy, and Wnt inhibitors may restore sensitivity.
Overall, available data indicate that Wnt signaling substantially impacts NSCLC tumorigenesis,
prognosis, and resistance to therapy, with loss of Wnt signaling inhibitors by promoter
hypermethylation or other mechanisms appearing to be particularly important. Wnt pathway
antagonists warrant exploration clinically in NSCLC. Agents blocking selected specific
β-catenin interactions and approaches to increase expression of downregulated Wnt
inhibitors may be of particular interest.