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Ref Type Journal Article
PMID (31337618)
Authors Schatoff EM, Goswami S, Zafra MP, Foronda M, Shusterman M, Leach BI, Katti A, Diaz BJ, Dow LE
Title Distinct Colorectal Cancer-Associated APC Mutations Dictate Response to Tankyrase Inhibition.
Journal Cancer discovery
Vol 9
Issue 10
Date 2019 Oct
URL
Abstract Text 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.This article is highlighted in the In This Issue feature, p. 1325.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
APC L852* colorectal cancer predicted - resistant G007-LK Preclinical Actionable In a preclinical study, G007-LK treatment did not alter gene expression pattern or affect growth in intestinal organoids established from mouse models of colorectal cancer driven by APC L850* (corresponding to L852* in human), and had no effect on tumor cell growth and differentiation in APC L850* mouse models (PMID: 31337618). 31337618
APC Q886* colorectal cancer predicted - resistant XAV939 Preclinical Actionable In a preclinical study, XAV939 treatment did not affect growth of mouse intestinal organoids expressing APC Q884* (corresponding to Q886* in human) in culture (PMID: 31337618). 31337618
APC Q886* colorectal cancer predicted - resistant G007-LK Preclinical Actionable In a preclinical study, G007-LK treatment did not alter gene expression pattern or affect growth in mouse intestinal organoids expressing APC Q884* (corresponding to Q886* in human) in culture (PMID: 31337618). 31337618
APC E582fs colorectal cancer predicted - resistant G007-LK Preclinical Actionable In a preclinical study, G007-LK treatment did not inhibited growth of mouse intestinal organoids expressing APC E580fs (corresponding to E582fs in human) in culture (PMID: 31337618). 31337618
APC Q1406* colorectal cancer predicted - sensitive XAV939 Preclinical Actionable In a preclinical study, XAV939 treatment inhibited growth of mouse intestinal organoids expressing APC Q1045* (corresponding to Q1046* in human) in culture (PMID: 31337618). 31337618
APC Q886* colorectal cancer predicted - resistant NVP-TNKS656 Preclinical Actionable In a preclinical study, NVP-TNKS656 treatment did not affect growth of mouse intestinal organoids expressing APC Q884* (corresponding to Q886* in human) in culture (PMID: 31337618). 31337618
CTNNB1 S33F colorectal cancer predicted - resistant G007-LK Preclinical Actionable In a preclinical study, G007-LK treatment did not alter gene expression pattern or affect growth in mouse intestinal organoids expressing CTNNB1 S33F (corresponding to S33F in human) in culture (PMID: 31337618). 31337618
APC Q1406* colorectal cancer predicted - sensitive G007-LK Preclinical Actionable In a preclinical study, G007-LK treatment altered gene expression pattern and inhibited growth of mouse intestinal organoids expressing APC Q1045* (corresponding to Q1046* in human) in culture (PMID: 31337618). 31337618
APC dec exp colorectal cancer predicted - sensitive G007-LK Preclinical Actionable In a preclinical study, G007-LK treatment altered gene expression pattern and induced growth arrest in intestinal organoids established from mouse models of colorectal cancer driven by APC knockdown, decreased proliferation and promoted differentiation in APC knockdown mouse models (PMID: 31337618). 31337618
APC Q1406* colorectal cancer predicted - sensitive NVP-TNKS656 Preclinical Actionable In a preclinical study, NVP-TNKS656 treatment inhibited growth of mouse intestinal organoids expressing APC Q1045* (corresponding to Q1046* in human) in culture (PMID: 31337618). 31337618