Potential signaling pathways as therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer

Abstract

Cases of mucinous ovarian cancer are predominantly resistant to chemotherapies. The present review summarizes current knowledge of the therapeutic potential of targeting the Wingless (WNT) pathway, with particular emphasis on preclinical and clinical studies, for improving the chemoresistance and treatment of mucinous ovarian cancer. A review was conducted of English language literature published between January 2000 and October 2017 that concerned potential signaling pathways associated with the chemoresistance of mucinous ovarian cancer. The literature indicated that aberrant activation of growth factor and WNT signaling pathways is specifically observed in mucinous ovarian cancer. An evolutionarily conserved signaling cascade system including epidermal growth factor/RAS/RAF/mitogen-activated protein kinase kinase/extracellular signal-regulated protein kinase, phosphoinositide 3-kinase/Akt and WNT signaling regulates a variety of cellular functions; their crosstalk mutually enhances signaling activity and induces chemoresistance. Novel antagonists, modulators and inhibitors have been developed for targeting the components of the WNT signaling pathway, namely Frizzled, low-density lipoprotein receptor-related protein 5/6, Dishevelled, casein kinase 1, AXIN, glycogen synthase kinase 3β and β-catenin. Targeted inhibition of WNT signaling represents a rational and promising novel approach to overcome chemoresistance, and several WNT inhibitors are being evaluated in preclinical studies. In conclusion, the WNT receptors and their downstream components may serve as novel therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer.

Keywords: WNT signaling; chemoresistance; mucinous ovarian cancer; therapeutic targets.

Figure 1.

Schematic diagram depicting the proposed WNT pathway antagonists, inhibitors and modulators. The WNT receptor and its downstream targets are considered as promising therapeutic targets for the treatment of mucinous ovarian cancer. Arrows indicate modulators. LRP5/6, lipoprotein receptor-related protein 5/6; Fzd, Frizzled; sFzd7, soluble Fzd7 peptide; RNF43, ring finger protein 43; DKK, Dickkopf1; DVL, Dishevelled; TMEM88, transmembrane protein 88; HUWE1, HECT, UBA and WWE domain-containing 1; WWOX, WW domain-containing oxidoreductase; DACT1, dishevelled-binding antagonist of β-catenin; GSK3β, glycogen synthase kinase 3β; DIF, differentiation-inducing factor; CK1, casein kinase 1; APC, adenomatous polyposis coli; CDX2, caudal type homeobox 2; TCF, T-cell factor; TNIK, Traf2 and Nck-interacting protein kinase.