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Ref Type Journal Article
PMID (37968472)
Authors Chen M, Mashima T, Oishi T, Muramatsu Y, Seto Y, Takamatsu M, Kawata N, Morino S, Nakamura A, Inaba S, Yuan X, Maruyama K, Suzuki M, Sato A, Yoshida H, Jang MK, Mizutani A, Takeuchi K, Yamaguchi K, Shirai F, Nagayama S, Katayama R, Seimiya H
Title APC/PIK3CA mutations and β-catenin status predict tankyrase inhibitor sensitivity of patient-derived colorectal cancer cells.
Journal Vol Issue Date Pages Journal Short Title
British journal of cancer 130 1 2024 Jan 151-162 Br J Cancer
URL
Abstract Text Aberrant WNT/β-catenin signaling drives carcinogenesis. Tankyrases poly(ADP-ribosyl)ate and destabilize AXINs, β-catenin repressors. Tankyrase inhibitors block WNT/β-catenin signaling and colorectal cancer (CRC) growth. We previously reported that 'short' APC mutations, lacking all seven β-catenin-binding 20-amino acid repeats (20-AARs), are potential predictive biomarkers for CRC cell sensitivity to tankyrase inhibitors. Meanwhile, 'Long' APC mutations, which possess more than one 20-AAR, do not predict inhibitor-resistant cells. Thus, additional biomarkers are needed to precisely predict the inhibitor sensitivity.Using 47 CRC patient-derived cells (PDCs), we examined correlations between the sensitivity to tankyrase inhibitors (G007-LK and RK-582), driver mutations, and the expressions of signaling factors. NOD.CB17-Prkdcscid/J and BALB/c-nu/nu xenograft mice were treated with RK-582.Short APC mutant CRC cells exhibited high/intermediate sensitivities to tankyrase inhibitors in vitro and in vivo. Active β-catenin levels correlated with inhibitor sensitivity in both short and long APC mutant PDCs. PIK3CA mutations, but not KRAS/BRAF mutations, were more frequent in inhibitor-resistant PDCs. Some wild-type APC PDCs showed inhibitor sensitivity in a β-catenin-independent manner.APC/PIK3CA mutations and β-catenin predict the sensitivity of APC-mutated CRC PDCs to tankyrase inhibitors. These observations may help inform the strategy of patient selection in future clinical trials of tankyrase inhibitors.

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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 S1356* colorectal cancer sensitive G007-LK Preclinical - Patient cell culture Actionable In a preclinical study, G007-LK inhibited viability of a patient-derived colorectal cancer cell line harboring APC S1356* in culture (PMID: 37968472). 37968472
APC R876* colorectal cancer sensitive Buparlisib + G007-LK Preclinical - Cell culture Actionable In a preclinical study, the combination of G007-LK and Buparlisib (BKM120) inhibited viability of a colorectal cancer patient-derived cell line harboring APC R876* in culture (PMID: 37968472). 37968472
APC G1116Efs*6 colorectal cancer sensitive G007-LK Preclinical - Cell culture Actionable In a preclinical study, G007-LK inhibited viability of a patient-derived colorectal cancer cell line harboring APC G1116Efs*6 in culture (PMID: 37968472). 37968472
APC K670* colorectal cancer sensitive G007-LK Preclinical - Cell culture Actionable In a preclinical study, G007-LK inhibited viability of a patient-derived colorectal cancer cell line harboring APC K670* in culture (PMID: 37968472). 37968472
APC S1421Rfs*52 colorectal cancer sensitive G007-LK Preclinical - Cell culture Actionable In a preclinical study, G007-LK inhibited viability of a patient-derived colorectal cancer cell line harboring APC S1421Rfs*52 in culture (PMID: 37968472). 37968472
APC R499* colorectal cancer sensitive G007-LK Preclinical - Patient cell culture Actionable In a preclinical study, G007-LK inhibited viability of a patient-derived colorectal cancer cell line harboring APC R499* in culture (PMID: 37968472). 37968472
APC V830Gfs*12 APC T1556Nfs*3 colorectal cancer resistant G007-LK Preclinical - Cell culture Actionable In a preclinical study, a patient-derived colorectal cancer cell line harboring APC V830Gfs*12 and T1556Nfs*3, along with PIK3CA E542K, was resistant to G007-LK treatment, as demonstrated by failure to inhibit viability in culture (PMID: 37968472). 37968472
APC L954* colorectal cancer sensitive G007-LK Preclinical - Cell culture Actionable In a preclinical study, G007-LK inhibited viability of a patient-derived colorectal cancer cell line harboring APC L954* in culture (PMID: 37968472). 37968472
APC S299Tfs*7 APC R805* colorectal cancer sensitive G007-LK Preclinical - Cell culture Actionable In a preclinical study, G007-LK inhibited viability of a patient-derived colorectal cancer cell line harboring APC R805* and S299Tfs*7 in culture (PMID: 37968472). 37968472
APC R302* APC E1345* colorectal cancer sensitive G007-LK + Trametinib Preclinical - Cell culture Actionable In a preclinical study, the addition of G007-LK to Mekinist (trametinib) treatment resulted in increased inhibition of viability compared to Mekinist (trametinib) alone in a colorectal cancer patient-derived cell line harboring APC R302* and E1345* in culture (PMID: 37968472). 37968472
APC Q886* colorectal cancer conflicting G007-LK Preclinical - Patient cell culture Actionable In a preclinical study, G007-LK inhibited viability of a patient-derived colorectal cancer cell line harboring APC Q886* in culture (PMID: 37968472). 37968472
APC Q1378* colorectal cancer sensitive G007-LK Preclinical - Patient cell culture Actionable In a preclinical study, G007-LK inhibited viability of a patient-derived colorectal cancer cell line harboring APC Q1378* in culture (PMID: 37968472). 37968472
APC E633* APC E1494* APC Q1529* colorectal cancer sensitive G007-LK Preclinical - Cell culture Actionable In a preclinical study, G007-LK inhibited viability of a patient-derived colorectal cancer cell line harboring APC E1494*, E633*, and Q1529* in culture (PMID: 37968472). 37968472
APC S1465Wfs*3 APC T1556Nfs*3 colorectal cancer sensitive G007-LK Preclinical - Cell culture Actionable In a preclinical study, G007-LK inhibited viability of a patient-derived colorectal cancer cell line harboring APC S1465Wfs*3 and T1556Nfs*3 in culture (PMID: 37968472). 37968472
APC R876* colorectal cancer sensitive G007-LK Preclinical - Patient cell culture Actionable In a preclinical study, G007-LK inhibited viability of a patient-derived colorectal cancer cell line harboring APC R876* in culture (PMID: 37968472). 37968472
APC R499* APC E1295* colorectal cancer sensitive G007-LK Preclinical - Cell culture Actionable In a preclinical study, G007-LK inhibited viability of a patient-derived colorectal cancer cell line harboring APC E1295* and R499* in culture (PMID: 37968472). 37968472
APC Q1367* colorectal cancer resistant G007-LK Preclinical - Patient cell culture Actionable In a preclinical study, a patient-derived colorectal cancer cell line harboring APC Q1367* was resistant to G007-LK treatment, as demonstrated by failure to inhibit viability in culture (PMID: 37968472). 37968472
APC R216* colorectal cancer sensitive G007-LK + Trametinib Preclinical - Cell culture Actionable In a preclinical study, the addition of G007-LK to Mekinist (trametinib) treatment resulted in increased inhibition of viability compared to Mekinist (trametinib) alone in a colorectal cancer patient-derived cell line harboring APC R216* in culture (PMID: 37968472). 37968472
APC Y935* APC L1489Yfs*18 colorectal cancer sensitive G007-LK Preclinical - Cell culture Actionable In a preclinical study, G007-LK inhibited viability of a patient-derived colorectal cancer cell line harboring APC L1489Yfs*18 and Y935* in culture (PMID: 37968472). 37968472
APC L665Ifs*8 APC R1450* colorectal cancer resistant G007-LK Preclinical - Cell culture Actionable In a preclinical study, a patient-derived colorectal cancer cell line harboring APC L665Ifs*8 and R1450* was resistant to G007-LK treatment, as demonstrated by failure to inhibit viability in culture (PMID: 37968472). 37968472
APC L1489* colorectal cancer sensitive G007-LK Preclinical - Cell culture Actionable In a preclinical study, G007-LK inhibited viability of a patient-derived colorectal cancer cell line harboring APC L1489* in culture (PMID: 37968472). 37968472
APC L1302Rfs*3 colorectal cancer resistant G007-LK Preclinical - Cell culture Actionable In a preclinical study, a patient-derived colorectal cancer cell line harboring APC L1302Rfs*3 was resistant to G007-LK treatment, as demonstrated by failure to inhibit viability in culture (PMID: 37968472). 37968472
APC I1287Rfs*3 colorectal cancer sensitive G007-LK Preclinical - Cell culture Actionable In a preclinical study, G007-LK inhibited viability of a patient-derived colorectal cancer cell line harboring APC I1287Rfs*3 in culture (PMID: 37968472). 37968472
APC E941* APC T1459fs colorectal cancer sensitive G007-LK + Trametinib Preclinical - Cell culture Actionable In a preclinical study, the addition of G007-LK to Mekinist (trametinib) treatment resulted in increased inhibition of viability compared to Mekinist (trametinib) alone in a colorectal cancer patient-derived cell line harboring APC E941* and T1459fs in culture (PMID: 37968472). 37968472