Research ArticleCancer therapy

Differential abundance of CK1α provides selectivity for pharmacological CK1α activators to target WNT-dependent tumors

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Science Signaling  27 Jun 2017:
Vol. 10, Issue 485, eaak9916
DOI: 10.1126/scisignal.aak9916

Treating WNT-driven tumors

The WNT signaling pathway powers the growth of various tumors, particularly colorectal cancer (CRC). However, WNT-targeted inhibitors are very toxic to normal gastrointestinal tissue, precluding their approval for clinical use. Li et al. show that WNT could be targeted by activating a kinase that inhibits the pathway. A small-molecule activator of the kinase CK1α called SSTC3 suppressed WNT activity in CRC cell lines, prevented tumor growth, and increased survival in mouse models of primary and metastatic CRC. Because the effects of SSTC3 were selective to cells with high WNT activity and low CK1α abundance, SSTC3 was minimally toxic to normal gastrointestinal epithelium. Thus, SSTC3 and its future derivatives may be a promising therapeutic for CRC patients.


Constitutive WNT activity drives the growth of various human tumors, including nearly all colorectal cancers (CRCs). Despite this prominence in cancer, no WNT inhibitor is currently approved for use in the clinic largely due to the small number of druggable signaling components in the WNT pathway and the substantial toxicity to normal gastrointestinal tissue. We have shown that pyrvinium, which activates casein kinase 1α (CK1α), is a potent inhibitor of WNT signaling. However, its poor bioavailability limited the ability to test this first-in-class WNT inhibitor in vivo. We characterized a novel small-molecule CK1α activator called SSTC3, which has better pharmacokinetic properties than pyrvinium, and found that it inhibited the growth of CRC xenografts in mice. SSTC3 also attenuated the growth of a patient-derived metastatic CRC xenograft, for which few therapies exist. SSTC3 exhibited minimal gastrointestinal toxicity compared to other classes of WNT inhibitors. Consistent with this observation, we showed that the abundance of the SSTC3 target, CK1α, was decreased in WNT-driven tumors relative to normal gastrointestinal tissue, and knocking down CK1α increased cellular sensitivity to SSTC3. Thus, we propose that distinct CK1α abundance provides an enhanced therapeutic index for pharmacological CK1α activators to target WNT-driven tumors.

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