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| Ref Type | Journal Article | ||||||||||||
| PMID | (28179481) | ||||||||||||
| Authors | Tanaka N, Mashima T, Mizutani A, Sato A, Aoyama A, Gong B, Yoshida H, Muramatsu Y, Nakata K, Matsuura M, Katayama R, Nagayama S, Fujita N, Sugimoto Y, Seimiya H | ||||||||||||
| Title | APC Mutations as a Potential Biomarker for Sensitivity to Tankyrase Inhibitors in Colorectal Cancer. | ||||||||||||
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| Abstract Text | In most colorectal cancers, Wnt/β-catenin signaling is activated by loss-of-function mutations in the adenomatous polyposis coli (APC) gene and plays a critical role in tumorigenesis. Tankyrases poly(ADP-ribosyl)ate and destabilize Axins, a negative regulator of β-catenin, and upregulate β-catenin signaling. Tankyrase inhibitors downregulate β-catenin and are expected to be promising therapeutics for colorectal cancer. However, colorectal cancer cells are not always sensitive to tankyrase inhibitors, and predictive biomarkers for the drug sensitivity remain elusive. Here we demonstrate that the short-form APC mutations predict the sensitivity of colorectal cancer cells to tankyrase inhibitors. By using well-established colorectal cancer cell lines, we found that tankyrase inhibitors downregulated β-catenin in the drug-sensitive, but not resistant, colorectal cancer cells. The drug-sensitive cells showed higher Tcf/LEF transcriptional activity than the resistant cells and possessed "short" truncated APCs lacking all seven β-catenin-binding 20-amino acid repeats (20-AARs). In contrast, the drug-resistant cells possessed "long" APC retaining two or more 20-AARs. Knockdown of the long APCs with two 20-AARs increased β-catenin, Tcf/LEF transcriptional activity and its target gene AXIN2 expression. Under these conditions, tankyrase inhibitors were able to downregulate β-catenin in the resistant cells. These results indicate that the long APCs are hypomorphic mutants, whereas they exert a dominant-negative effect on Axin-dependent β-catenin degradation caused by tankyrase inhibitors. Finally, we established 16 patient-derived colorectal cancer cells and confirmed that the tankyrase inhibitor-responsive cells harbor the short-form APC mutations. These observations exemplify the predictive importance of APC mutations, the most common genetic alteration in colorectal cancers, for molecular targeted therapeutics. Mol Cancer Ther; 16(4); 752-62. ©2017 AACR. | ||||||||||||
| 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 |
|---|---|---|---|---|---|
| APC | N1819fs | frameshift | unknown | APC N1819fs results in a change in the amino acid sequence of the Apc protein beginning at aa 1819 of 2843, likely resulting in premature truncation of the functional protein (UniProt.org). N1819fs has been identified in the scientific literature (PMID: 28179481), but has not been biochemically characterized and therefore, its effect on Apc protein function is unknown (PubMed, Aug 2024). | |
| APC | S811* | nonsense | loss of function | APC S811* results in a premature truncation of the Apc protein at amino acid 811 of 2843 (UniProt.org). S811* retains binding with Axin1 but confers a loss of function to Apc as demonstrated by decreased beta-catenin recruitment, phosphorylation, and ubiquitination in culture (PMID: 34352208), and activation of Wnt signaling in reporter assays (PMID: 28179481). |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| APC S1197* APC S1278* | colorectal cancer | sensitive | XAV939 | Preclinical - Cell culture | Actionable | In a preclinical study, XAV939 inhibited growth of a colorectal cancer cell line harboring APC S1197* and APC S1278* in culture (PMID: 28179481). | 28179481 |
| APC E853* APC T1556fs | colorectal cancer | resistant | XAV939 | Preclinical - Cell culture | Actionable | In a preclinical study, a colorectal cancer cell line harboring APC E853* and APC T1556fs (reported as APC T1556fs*3) demonstrated low levels of Tcf/LEF activity, and was resistant to treatment with XAV939 in culture (PMID: 28179481). | 28179481 |
| APC S811* | colorectal cancer | sensitive | XAV939 | Preclinical - Cell culture | Actionable | In a preclinical study, XAV939 inhibited growth of a colorectal cancer cell line harboring APC S811* in culture (PMID: 28179481). | 28179481 |
| APC I1164fs | colorectal cancer | sensitive | G007-LK | Preclinical - Patient cell culture | Actionable | In a preclinical study, G007-LK inhibited growth of a patient-derived colorectal cancer cell line harboring APC I1164fs in culture (PMID: 28179481). | 28179481 |
| APC S811* | colorectal cancer | sensitive | IWR-1 | Preclinical - Cell culture | Actionable | In a preclinical study, treatment with IWR-1 decreased active beta-catenin levels and reduced growth of a colorectal cancer cell line harboring APC S811* in culture (PMID: 28179481). | 28179481 |
| APC N1819fs APC wild-type | colorectal cancer | resistant | G007-LK | Preclinical - Cell culture | Actionable | In a preclinical study, a colorectal cancer cell line harboring APC N1819fs (reported as N1819fs*7) and a wild-type copy of APC demonstrated low levels of Tcf/LEF activity, and was resistant to treatment with G007-LK in culture (PMID: 28179481). | 28179481 |
| APC W553* | colorectal cancer | sensitive | IWR-1 | Preclinical - Cell culture | Actionable | In a preclinical study, IWR-1 inhibited growth of a patient-derived colorectal cancer cell line harboring APC W553* in culture (PMID: 28179481). | 28179481 |
| APC E853* APC T1556fs | colorectal cancer | resistant | G007-LK | Preclinical - Cell culture | Actionable | In a preclinical study, a colorectal cancer cell line harboring APC E853* and APC T1556fs (reported as APC T1556fs*3) demonstrated low levels of Tcf/LEF activity, and was resistant to treatment with G007-LK in culture (PMID: 28179481). | 28179481 |
| APC N1819fs APC wild-type | colorectal cancer | resistant | XAV939 | Preclinical - Cell culture | Actionable | In a preclinical study, a colorectal cancer cell line harboring APC N1819fs (reported as N1819fs*7) and a wild-type copy of APC demonstrated low levels of Tcf/LEF activity, and was resistant to treatment with XAV939 in culture (PMID: 28179481). | 28179481 |
| APC S811* | colorectal cancer | sensitive | G007-LK | Preclinical - Cell culture | Actionable | In a preclinical study, treatment with G007-LK decreased active beta-catenin levels and Tcf/LEF activity, and reduced growth of a colorectal cancer cell line harboring APC S811* in culture (PMID: 28179481). | 28179481 |
| APC N1819fs | colorectal cancer | resistant | IWR-1 | Preclinical - Cell culture | Actionable | In a preclinical study, a colorectal cancer cell line harboring APC N1819fs (reported as N1819fs*7) and a wild-type copy of APC demonstrated low levels of Tcf/LEF activity, and was resistant to treatment with IWR-1 in culture (PMID: 28179481). | 28179481 |
| APC E853* APC T1556fs | colorectal cancer | resistant | IWR-1 | Preclinical - Cell culture | Actionable | In a preclinical study, a colorectal cancer cell line harboring APC E853* and APC T1556fs (reported as APC T1556fs*3) demonstrated low levels of Tcf/LEF activity, and was resistant to treatment with IWR-1 in culture (PMID: 28179481). | 28179481 |
| APC S1197* APC S1278* | colorectal cancer | sensitive | G007-LK | Preclinical - Cell culture | Actionable | In a preclinical study, treatment with G007-LK decreased active beta-catenin levels and Tcf/LEF activity, and reduced growth of a colorectal cancer cell line harboring APC S1197* and APC S1278* in culture (PMID: 28179481). | 28179481 |
| APC S1197* APC S1278* | colorectal cancer | sensitive | IWR-1 | Preclinical - Cell culture | Actionable | In a preclinical study, treatment with IWR-1 decreased active beta-catenin levels and Tcf/LEF activity, and reduced growth of a colorectal cancer cell line harboring APC S1197* and APC S1278* in culture (PMID: 28179481). | 28179481 |
| APC W553* | colorectal cancer | sensitive | G007-LK | Preclinical - Cell culture | Actionable | In a preclinical study, G007-LK inhibited growth of a patient-derived colorectal cancer cell line harboring APC W553* in culture (PMID: 28179481). | 28179481 |
| APC L665* APC R1450* | colorectal cancer | sensitive | IWR-1 | Preclinical - Cell culture | Actionable | In a preclinical study, a colorectal cancer cell line harboring APC L665* and APC R1450* demonstrated low levels of Tcf/LEF activity, and was resistant to treatment with IWR-1 in culture (PMID: 28179481). | 28179481 |
| APC I1164fs | colorectal cancer | sensitive | IWR-1 | Preclinical - Cell culture | Actionable | In a preclinical study, IWR-1 inhibited growth of a patient-derived colorectal cancer cell line harboring APC I1164fs in culture (PMID: 28179481). | 28179481 |
| APC R216* | colorectal cancer | sensitive | IWR-1 | Preclinical - Cell culture | Actionable | In a preclinical study, IWR-1 inhibited growth of a patient-derived colorectal cancer cell line harboring APC R216* in culture (PMID: 28179481). | 28179481 |
| APC L665* APC R1450* | colorectal cancer | sensitive | XAV939 | Preclinical - Cell culture | Actionable | In a preclinical study, a colorectal cancer cell line harboring APC L665* and APC R1450* demonstrated low levels of Tcf/LEF activity, and was resistant to treatment with XAV939 in culture (PMID: 28179481). | 28179481 |
| APC L665* APC R1450* | colorectal cancer | resistant | G007-LK | Preclinical - Cell culture | Actionable | In a preclinical study, a colorectal cancer cell line harboring APC L665* and APC R1450* demonstrated low levels of Tcf/LEF activity, and was resistant to treatment with G007-LK in culture (PMID: 28179481). | 28179481 |
| APC R216* | colorectal cancer | sensitive | G007-LK | Preclinical - Cell culture | Actionable | In a preclinical study, a patient-derived colorectal cancer cell line harboring APC R216* demonstrated sensitivity to G007-LK in culture (PMID: 28179481). | 28179481 |