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

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 progra

SUBMITTER: Schatoff EM 

PROVIDER: S-EPMC6774804 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature