Editors' ChoiceCancer

A useful off-target effect

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Sci. Signal.  23 Aug 2016:
Vol. 9, Issue 442, pp. ec192
DOI: 10.1126/scisignal.aai8400

Axitinib is a tyrosine kinase inhibitor that is used to treat some forms of cancer because it targets several receptors that stimulate angiogenesis. In a screen of clinically approved drugs that inhibited Wnt signaling in cultured human prostate cells, Qu et al. found that axitinib promoted destruction of the Wnt-responsive transcription factor β-catenin. In the absence of a Wnt signal, β-catenin is targeted for destruction through a complex that contains the tumor suppressor APC (adenomatous polyposis coli) and the E3 ubiquitin ligase βTrCP (β-transducin repeats–containing protein). Wnt signaling inhibits the destruction complex, thus stabilizing β-catenin and enabling it to enter the nucleus to regulate gene expression. Axitinib blocked Wnt signaling in several assays in cultured human colon cancer cells and in zebrafish, and oral administration of axitinib reduced adenoma formation in Apc+/– mice. Axitinib reduced the abundance of β-catenin in colon cancer cells in a manner dependent on the proteasome but not dependent on APC or βTrCP. The cultured cells used in these experiments did not have receptors known to be targeted by axitinib; therefore the authors isolated proteins from these cells that bound to axitinib in vitro. Binding to axitinib increased the thermal stability of the E3 ubiquitin ligase SHPRH (SNF2, histone-linker, PHD and RING finger domain–containing helicase). Overexpressing SHPRH in colon cancer cells reduced the abundance of endogenous β-catenin as well as forms of β-catenin that cannot be targeted for degradation by the APC destruction complex. In the presence of a proteasome inhibitor, wild-type SHPRH increased the ubiquitylation of β-catenin, but a catalytically impaired form of SHPRH did not. Depleting SHPRH by RNA interference increased the abundance of β-catenin and prevented the axitinib-induced reduction of β-catenin. These findings identify an off-target effect of axitinib that may be useful for treating cancers driven by aberrant Wnt signaling, including those in which the function of the APC complex is impaired.

Y. Qu, N. Gharbi, X. Yuan, J. R. Olsen, P. Blicher, B. Dalhus, K. A. Brokstad, B. Lin, A. M. Øyan, W. Zhang, K.-H. Kalland, X. Ke, Axitinib blocks Wnt/β-catenin signaling and directs asymmetric cell division in cancer. Proc. Natl. Acad. Sci. U.S.A. 113, 9339–9344 (2016). [PubMed]