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Cancer Discov. 2019 Jul 23. doi: 10.1158/2159-8290.CD-19-0289. [Epub ahead of print]

Distinct Colorectal Cancer-Associated APC Mutations Dictate Response to Tankyrase Inhibition.

Author information

1
Sandra and Edward Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, New York, New York.
2
Weill Cornell/Rockefeller/Sloan Kettering Tri-I MD-PhD program, New York, New York.
3
Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, New York.
4
Sandra and Edward Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, New York, New York. lud2005@med.cornell.edu.
5
Department of Biochemistry, Weill Cornell Medicine, New York, New York.

Abstract

The majority of colorectal cancers show hyperactivated WNT signaling due to inactivating mutations in the adenomatous polyposis coli (APC) tumor suppressor. Genetically restoring APC suppresses WNT and induces rapid and sustained tumor regression, implying that reengaging this endogenous tumor-suppressive mechanism may be an effective therapeutic strategy. Here, using new animal models, human cell lines, and ex vivo organoid cultures, we show that Tankyrase (TNKS) inhibition can control WNT hyperactivation and provide long-term tumor control in vivo, but that effective responses are critically dependent on how APC is disrupted. Mutant APC proteins truncated within the mutation cluster region physically engage the destruction complex and suppress the WNT transcriptional program, while APC variants with early truncations (e.g., Apc Min) show limited interaction with AXIN1 and β-catenin, and do not respond to TNKS blockade. Together, this work shows that TNKS inhibition, like APC restoration, can reestablish endogenous control of WNT/β-catenin signaling, but that APC genotype is a crucial determinant of this response. SIGNIFICANCE: This study reveals how subtle changes to the mutations in a critical colorectal tumor suppressor, APC, influence the cellular response to a targeted therapy. It underscores how investigating the specific genetic alterations that occur in human cancer can identify important biological mechanisms of drug response and resistance.

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