Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	9	10	2019 Oct	1358-1371	Cancer Discov

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 E582fs	colorectal cancer	predicted - resistant	G007-LK	Preclinical	Actionable	In a preclinical study, G007-LK treatment did not inhibit growth of mouse intestinal organoids expressing APC E580fs (corresponding to E582fs in human) in culture (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
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	conflicting	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
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 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
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 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	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