Differential abundance of CK1a provides selectivity for pharmacological CK1a activators to target WNT-dependent tumors

Bin Li, Darren Orton, Leif R. Neitzel, Luisana Astudillo, Chen Shen, Jun Long, Xi Chen, Kellye C. Kirkbride, Thomas Doundoulakis, Marcy L. Guerra, Julia Zaias, Dennis Liang Fei, Jezabel Rodriguez-Blanco, Curtis Thorne, Zhiqiang Wang, Ke Jin, Dao Nguyen, Laurence Sands, Floriano Marchetti, Maria T AbreuMelanie H. Cobb, Anthony J Capobianco, Ethan Lee, David J. Robbin

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

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 1a (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 CK1a activators to target WNT-driven tumors.

Original languageEnglish (US)
Article numberaak9916
JournalScience Signaling
Volume10
Issue number485
DOIs
StatePublished - Jun 27 2017

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Li, B., Orton, D., Neitzel, L. R., Astudillo, L., Shen, C., Long, J., Chen, X., Kirkbride, K. C., Doundoulakis, T., Guerra, M. L., Zaias, J., Fei, D. L., Rodriguez-Blanco, J., Thorne, C., Wang, Z., Jin, K., Nguyen, D., Sands, L., Marchetti, F., ... Robbin, D. J. (2017). Differential abundance of CK1a provides selectivity for pharmacological CK1a activators to target WNT-dependent tumors. Science Signaling, 10(485), [aak9916]. https://doi.org/10.1126/scisignal.aak9916