Wnt/β-catenin signaling in the development and therapeutic resistance of non-small cell lung cancer

Abstract

Wnt/β-catenin signaling is a critical pathway that influences development and therapeutic response of non-small cell lung cancer (NSCLC). In recent years, many Wnt regulators, including proteins, miRNAs, lncRNAs, and circRNAs, have been found to promote or inhibit signaling by acting on Wnt proteins, receptors, signal transducers and transcriptional effectors. The identification of these regulators and their underlying molecular mechanisms provides important implications for how to target this pathway therapeutically. In this review, we summarize recent studies of Wnt regulators in the development and therapeutic response of NSCLC.

Keywords: Cancer development; Non-small cell lung cancer; Therapeutic response; Wnt/β-catenin signaling.

Fig. 1

An overview of Wnt/β-catenin signaling pathway. a In the absence of the Wnt signal, cytosolic β-catenin is phosphorylated by kinases CK1α and GSK3β with the help of scaffolding proteins AXIN and APC. Phosphorylation of β-catenin leads to its ubiquitylation and subsequent proteasomal degradation. b Wnt ligands bind FZD and LRP5/6 receptors on the cell surface. Subsequent phosphorylation of LRP5/6 and recruitment of signal transducers DVL and AXIN to the Wnt-bound receptors facilitate inhibition of GSK3β activity. This inhibition blocks phosphorylation and degradation of β-catenin, leading to β-catenin accumulation in the cytoplasm and translocation into the nucleus. In the nucleus, β-catenin interacts with TCF/LEF transcription factors to activate Wnt target genes

Fig. 2

APC and CTNNB1 mutations identified in NSCLC from GENIE datasets (GENIE 14.0-public, n = 26,473). a The recurrent truncating APC mutations (n ≥ 2) in NSCLC were shown on the schematic structure. The truncating mutations include nonsense mutations and frameshift mutations. b The recurrent CTNNB1 mutations (n ≥ 2) were shown on the schematic structure. β-catenin is sequestered in the destruction complex and sequentially phosphorylated by CK1α at Ser45 and GSK3β at Ser33/Ser37/Thr41, respectively. The truncating mutations were not included in this study