Reference Detail

Ref Type Journal Article
PMID (23539443)
Authors Lau T, Chan E, Callow M, Waaler J, Boggs J, Blake RA, Magnuson S, Sambrone A, Schutten M, Firestein R, Machon O, Korinek V, Choo E, Diaz D, Merchant M, Polakis P, Holsworth DD, Krauss S, Costa M
Title A novel tankyrase small-molecule inhibitor suppresses APC mutation-driven colorectal tumor growth.
Journal Cancer research
Vol 73
Issue 10
Date 2013 May 15
URL
Abstract Text Most colorectal cancers (CRC) are initiated by mutations of APC, leading to increased β-catenin-mediated signaling. However, continued requirement of Wnt/β-catenin signaling for tumor progression in the context of acquired KRAS and other mutations is less well-established. To attenuate Wnt/β-catenin signaling in tumors, we have developed potent and specific small-molecule tankyrase inhibitors, G007-LK and G244-LM, that reduce Wnt/β-catenin signaling by preventing poly(ADP-ribosyl)ation-dependent AXIN degradation, thereby promoting β-catenin destabilization. We show that novel tankyrase inhibitors completely block ligand-driven Wnt/β-catenin signaling in cell culture and display approximately 50% inhibition of APC mutation-driven signaling in most CRC cell lines. It was previously unknown whether the level of AXIN protein stabilization by tankyrase inhibition is sufficient to impact tumor growth in the absence of normal APC activity. Compound G007-LK displays favorable pharmacokinetic properties and inhibits in vivo tumor growth in a subset of APC-mutant CRC xenograft models. In the xenograft model most sensitive to tankyrase inhibitor, COLO-320DM, G007-LK inhibits cell-cycle progression, reduces colony formation, and induces differentiation, suggesting that β-catenin-dependent maintenance of an undifferentiated state may be blocked by tankyrase inhibition. The full potential of the antitumor activity of G007-LK may be limited by intestinal toxicity associated with inhibition of Wnt/β-catenin signaling and cell proliferation in intestinal crypts. These results establish proof-of-concept antitumor efficacy for tankyrase inhibitors in APC-mutant CRC models and uncover potential diagnostic and safety concerns to be overcome as tankyrase inhibitors are advanced into the clinic.

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Molecular Profile Treatment Approach
APC S1355fs Tankyrase Inhibitor
APC R1114* Tankyrase Inhibitor
APC I1307Kfs*14 Tankyrase Inhibitor
APC I1307fs Tankyrase Inhibitor
APC K1370* Tankyrase Inhibitor
APC P1319fs Tankyrase Inhibitor
APC N1455fs Tankyrase Inhibitor
APC G1499* Tankyrase Inhibitor
APC E1309* Tankyrase Inhibitor
APC E1554fs Tankyrase Inhibitor
APC E1374* Tankyrase Inhibitor
APC E1552* Tankyrase Inhibitor
APC E1554* Tankyrase Inhibitor
APC D1318fs Tankyrase Inhibitor
APC L795Sfs*25 Tankyrase Inhibitor
APC L665* Tankyrase Inhibitor
APC S1315fs Tankyrase Inhibitor
APC R232* Tankyrase Inhibitor
APC K1308* Tankyrase Inhibitor
APC S1197* Tankyrase Inhibitor
APC P1372fs Tankyrase Inhibitor
APC C207* Tankyrase Inhibitor
APC S1346* Tankyrase Inhibitor
APC S1364fs Tankyrase Inhibitor
APC S31fs Tankyrase Inhibitor
APC C1410* Tankyrase Inhibitor
APC S1356fs Tankyrase Inhibitor
APC R1435fs Tankyrase Inhibitor
APC Y737* Tankyrase Inhibitor
APC E853* Tankyrase Inhibitor
APC T1438fs Tankyrase Inhibitor
APC A1485fs Tankyrase Inhibitor
APC A952Qfs*10 Tankyrase Inhibitor
APC P1443Lfs*30 Tankyrase Inhibitor
APC A1446fs Tankyrase Inhibitor
APC E1464fs Tankyrase Inhibitor
APC A1475fs Tankyrase Inhibitor
APC E1309fs Tankyrase Inhibitor
APC D1297fs Tankyrase Inhibitor
APC D1486fs Tankyrase Inhibitor
APC Q1303fs Tankyrase Inhibitor
APC R1450* Tankyrase Inhibitor
APC R876* Tankyrase Inhibitor
APC E1397* Tankyrase Inhibitor
APC K1555* Tankyrase Inhibitor
APC Q1378* Tankyrase Inhibitor
APC Q1127* Tankyrase Inhibitor
APC A928fs Tankyrase Inhibitor
APC P1373fs Tankyrase Inhibitor
APC Q1294* Tankyrase Inhibitor
APC M1525Lfs*39 Tankyrase Inhibitor
APC Q1406* Tankyrase Inhibitor
APC P1458fs Tankyrase Inhibitor
APC C1274fs Tankyrase Inhibitor
APC E1464* Tankyrase Inhibitor
APC G471* Tankyrase Inhibitor
APC G1312* Tankyrase Inhibitor
APC S1436fs Tankyrase Inhibitor
APC K716* Tankyrase Inhibitor
APC A1296fs Tankyrase Inhibitor
APC Q886* Tankyrase Inhibitor
APC Y1376* Tankyrase Inhibitor
APC G1357fs Tankyrase Inhibitor
APC E763* Tankyrase Inhibitor
APC A1351fs Tankyrase Inhibitor
APC F1491fs Tankyrase Inhibitor
APC Q1338* Tankyrase Inhibitor
APC Q1294fs Tankyrase Inhibitor
APC S1356* Tankyrase Inhibitor
APC E1513* Tankyrase Inhibitor
APC I1557fs Tankyrase Inhibitor
APC S1315* Tankyrase Inhibitor
APC T1301fs Tankyrase Inhibitor
APC E1577* Tankyrase Inhibitor
APC N869fs Tankyrase Inhibitor
APC E1306fs Tankyrase Inhibitor
APC E1379* Tankyrase Inhibitor
APC S1465fs Tankyrase Inhibitor
APC W553* Tankyrase Inhibitor
APC Q1291* Tankyrase Inhibitor
APC Q1469* Tankyrase Inhibitor
APC L1488* Tankyrase Inhibitor
APC E1451* Tankyrase Inhibitor
APC D1394fs Tankyrase Inhibitor
APC Q424* Tankyrase Inhibitor
APC Q1131* Tankyrase Inhibitor
APC E1345* Tankyrase Inhibitor
APC T621Lfs*9 Tankyrase Inhibitor
APC P1453fs Tankyrase Inhibitor
APC Q1067* Tankyrase Inhibitor
APC A1492fs Tankyrase Inhibitor
APC Q1447* Tankyrase Inhibitor
APC S1215* Tankyrase Inhibitor
APC R1314fs Tankyrase Inhibitor
APC E1408* Tankyrase Inhibitor
APC S811* Tankyrase Inhibitor
APC N1300fs Tankyrase Inhibitor
APC K1310* Tankyrase Inhibitor
APC inact mut Tankyrase Inhibitor
APC R302* Tankyrase Inhibitor
APC I1311fs Tankyrase Inhibitor
APC K1350* Tankyrase Inhibitor
APC C1387* Tankyrase Inhibitor
APC D1425fs Tankyrase Inhibitor
APC H1375fs Tankyrase Inhibitor
APC R1399Ffs*9 Tankyrase Inhibitor
APC G1416* Tankyrase Inhibitor
APC T1493fs Tankyrase Inhibitor
APC Q1096* Tankyrase Inhibitor
APC L1489fs Tankyrase Inhibitor
APC E1544* Tankyrase Inhibitor
APC E1309Afs*3 Tankyrase Inhibitor
APC E1322* Tankyrase Inhibitor
APC A1305fs Tankyrase Inhibitor
APC S1411fs Tankyrase Inhibitor
APC I606fs Tankyrase Inhibitor
APC E1317* Tankyrase Inhibitor
APC E868* Tankyrase Inhibitor
APC R216* Tankyrase Inhibitor
APC A1325fs Tankyrase Inhibitor
APC R564* Tankyrase Inhibitor
APC C1387fs Tankyrase Inhibitor
APC S1495fs Tankyrase Inhibitor
APC Y935* Tankyrase Inhibitor
APC T1301Pfs*4 Tankyrase Inhibitor
APC G1312fs Tankyrase Inhibitor
APC R554* Tankyrase Inhibitor
APC W421* Tankyrase Inhibitor
APC S1400* Tankyrase Inhibitor
APC Q1429* Tankyrase Inhibitor
APC R213* Tankyrase Inhibitor
APC E1494fs Tankyrase Inhibitor
APC E658* Tankyrase Inhibitor
APC N1455Ifs*18 Tankyrase Inhibitor
APC E190* Tankyrase Inhibitor
APC L1564* Tankyrase Inhibitor
APC N1026S Tankyrase Inhibitor
APC R283* Tankyrase Inhibitor
APC A1470fs Tankyrase Inhibitor
APC V1377fs Tankyrase Inhibitor
APC L684* Tankyrase Inhibitor
APC Q1480* Tankyrase Inhibitor
APC T1445fs Tankyrase Inhibitor
APC Q1378fs Tankyrase Inhibitor
APC S1465Wfs*3 Tankyrase Inhibitor
APC I1164fs Tankyrase Inhibitor
APC D1422fs Tankyrase Inhibitor
APC K1449fs Tankyrase Inhibitor
APC R640G Tankyrase Inhibitor
APC E1295* Tankyrase Inhibitor
APC R499* Tankyrase Inhibitor
APC K1310fs Tankyrase Inhibitor
APC F1354fs Tankyrase Inhibitor
APC A1471fs Tankyrase Inhibitor
APC H1490fs Tankyrase Inhibitor
APC T1496fs Tankyrase Inhibitor
APC P1361fs Tankyrase Inhibitor
APC P1497fs Tankyrase Inhibitor
APC T1556fs Tankyrase Inhibitor
APC T1459fs Tankyrase Inhibitor
APC P1483fs Tankyrase Inhibitor
APC K1462fs Tankyrase Inhibitor
APC Q1444* Tankyrase Inhibitor
APC P950Afs*13 Tankyrase Inhibitor
APC A1316fs Tankyrase Inhibitor
APC R405* Tankyrase Inhibitor
APC K1817fs Tankyrase Inhibitor
APC P1439fs Tankyrase Inhibitor
APC E1547* Tankyrase Inhibitor
APC R1348fs Tankyrase Inhibitor
APC R1435* Tankyrase Inhibitor
APC E1461* Tankyrase Inhibitor
APC D1484fs Tankyrase Inhibitor
APC Q1367* Tankyrase Inhibitor
APC P1440fs Tankyrase Inhibitor
APC A1402fs Tankyrase Inhibitor
APC L1488fs Tankyrase Inhibitor
APC K1555fs Tankyrase Inhibitor
APC E1306* Tankyrase Inhibitor
APC L1488Ffs*26 Tankyrase Inhibitor
APC E1353* Tankyrase Inhibitor
APC P1443fs Tankyrase Inhibitor
APC N741fs Tankyrase Inhibitor
APC E1309Dfs*4 Tankyrase Inhibitor
APC M1431fs Tankyrase Inhibitor
APC C1578fs Tankyrase Inhibitor
APC Q1303* Tankyrase Inhibitor
APC C1289fs Tankyrase Inhibitor
APC S1278* Tankyrase Inhibitor
APC Y1376fs Tankyrase Inhibitor
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
G007-LK G007-LK 10 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
G007-LK Tankyrase Inhibitor 9 G007-LK inhibits tankyrase, which leads to stabilization of AXIN, thereby resulting in degradation of beta-catenin and decreased growth of APC-deficient tumors (PMID: 23539443).
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 inact mut colon cancer sensitive G007-LK Preclinical - Cell line xenograft Actionable In a preclinical study, G007-LK inhibited growth of APC-mutant colorectal cancer cell lines in culture and in xenograft models (PMID: 23539443). 23539443