@misc{10481/110845,
year = {2019},
month = {10},
url = {https://hdl.handle.net/10481/110845},
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., ApcMin) 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.},
organization = {NIH/NCI (CA195787-01, U54OD020355, P30 CA0088748, 1 F31 CA224800-01, T32 CA203702, CA 181280-01)},
organization = {Stand Up To Cancer (SU2C-AACR-DT22-17)},
organization = {American Association for Cancer Research},
organization = {National Institute of General Medical Sciences (T32GM07739)},
publisher = {American Association for Cancer Research},
keywords = {Colorectal cancer},
keywords = {APC mutations},
keywords = {Tankyrase inhibitors},
title = {Distinct Colorectal Cancer–Associated APC Mutations Dictate Response to Tankyrase Inhibition},
doi = {10.1158/2159-8290.CD-19-0289},
author = {Schatoff, Emma M and Goswami, Sunkanya and Zafra, Maria Paz and Foronda, Miguel and Shusterman, Michael and Leach, Benjamin I and Katti, Alyna and Diaz, Bianca J and Dow, Lukas E},
}