Reference Detail

Ref Type Journal Article
PMID (23621985)
Authors Busch AM, Johnson KC, Stan RV, Sanglikar A, Ahmed Y, Dmitrovsky E, Freemantle SJ
Title Evidence for tankyrases as antineoplastic targets in lung cancer.
Journal BMC cancer
Vol 13
Issue
Date 2013 Apr 28
URL
Abstract Text New pharmacologic targets are urgently needed to treat or prevent lung cancer, the most common cause of cancer death for men and women. This study identified one such target. This is the canonical Wnt signaling pathway, which is deregulated in cancers, including those lacking adenomatous polyposis coli or β-catenin mutations. Two poly-ADP-ribose polymerase (PARP) enzymes regulate canonical Wnt activity: tankyrase (TNKS) 1 and TNKS2. These enzymes poly-ADP-ribosylate (PARsylate) and destabilize axin, a key component of the β-catenin phosphorylation complex.This study used comprehensive gene profiles to uncover deregulation of the Wnt pathway in murine transgenic and human lung cancers, relative to normal lung. Antineoplastic consequences of genetic and pharmacologic targeting of TNKS in murine and human lung cancer cell lines were explored, and validated in vivo in mice by implantation of murine transgenic lung cancer cells engineered with reduced TNKS expression relative to controls.Microarray analyses comparing Wnt pathway members in malignant versus normal tissues of a murine transgenic cyclin E lung cancer model revealed deregulation of Wnt pathway components, including TNKS1 and TNKS2. Real-time PCR assays independently confirmed these results in paired normal-malignant murine and human lung tissues. Individual treatments of a panel of human and murine lung cancer cell lines with the TNKS inhibitors XAV939 and IWR-1 dose-dependently repressed cell growth and increased cellular axin 1 and tankyrase levels. These inhibitors also repressed expression of a Wnt-responsive luciferase construct, implicating the Wnt pathway in conferring these antineoplastic effects. Individual or combined knockdown of TNKS1 and TNKS2 with siRNAs or shRNAs reduced lung cancer cell growth, stabilized axin, and repressed tumor formation in murine xenograft and syngeneic lung cancer models.Findings reported here uncovered deregulation of specific components of the Wnt pathway in both human and murine lung cancer models. Repressing TNKS activity through either genetic or pharmacological approaches antagonized canonical Wnt signaling, reduced murine and human lung cancer cell line growth, and decreased tumor formation in mouse models. Taken together, these findings implicate the use of TNKS inhibitors to target the Wnt pathway to combat lung cancer.

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Molecular Profile Treatment Approach
CTNNB1 S45Y Tankyrase Inhibitor
CTNNB1 A43P Tankyrase Inhibitor
CTNNB1 A39G Tankyrase Inhibitor
CTNNB1 S37Y Tankyrase Inhibitor
CTNNB1 T41A Tankyrase Inhibitor
CTNNB1 S37P Tankyrase Inhibitor
CTNNB1 D32A Tankyrase Inhibitor
CTNNB1 S33F Tankyrase Inhibitor
CTNNB1 G48D Tankyrase Inhibitor
CTNNB1 S45T Tankyrase Inhibitor
CTNNB1 S33T Tankyrase Inhibitor
CTNNB1 S45N Tankyrase Inhibitor
CTNNB1 S45F Tankyrase Inhibitor
CTNNB1 D32E Tankyrase Inhibitor
CTNNB1 E54K Tankyrase Inhibitor
CTNNB1 S37T Tankyrase Inhibitor
CTNNB1 A13T Tankyrase Inhibitor
CTNNB1 G34V Tankyrase Inhibitor
CTNNB1 G34R Tankyrase Inhibitor
CTNNB1 S37C Tankyrase Inhibitor
CTNNB1 S45A Tankyrase Inhibitor
CTNNB1 E67K Tankyrase Inhibitor
CTNNB1 H36Y Tankyrase Inhibitor
CTNNB1 S33A Tankyrase Inhibitor
CTNNB1 D32H Tankyrase Inhibitor
CTNNB1 S45P Tankyrase Inhibitor
CTNNB1 G34E Tankyrase Inhibitor
CTNNB1 S45C Tankyrase Inhibitor
CTNNB1 S33C Tankyrase Inhibitor
CTNNB1 S37A Tankyrase Inhibitor
CTNNB1 P44A Tankyrase Inhibitor
CTNNB1 S33P Tankyrase Inhibitor
CTNNB1 P44_S45del Tankyrase Inhibitor
CTNNB1 K335I Tankyrase Inhibitor
CTNNB1 D32V Tankyrase Inhibitor
CTNNB1 S33N Tankyrase Inhibitor
CTNNB1 A43T Tankyrase Inhibitor
CTNNB1 act mut Tankyrase Inhibitor
CTNNB1 S33Y Tankyrase Inhibitor
CTNNB1 T41I Tankyrase Inhibitor
CTNNB1 G34A Tankyrase Inhibitor
CTNNB1 S45del Tankyrase Inhibitor
CTNNB1 I35S Tankyrase Inhibitor
CTNNB1 H36P Tankyrase Inhibitor
CTNNB1 A21T Tankyrase Inhibitor
CTNNB1 D32N Tankyrase Inhibitor
CTNNB1 W383R Tankyrase Inhibitor
CTNNB1 D32G Tankyrase Inhibitor
CTNNB1 S37F Tankyrase Inhibitor
CTNNB1 V22A Tankyrase Inhibitor
CTNNB1 S33L Tankyrase Inhibitor
CTNNB1 W25_D32del Tankyrase Inhibitor
CTNNB1 I35T Tankyrase Inhibitor
CTNNB1 A39T Tankyrase Inhibitor
CTNNB1 N387K Tankyrase Inhibitor
CTNNB1 D32Y Tankyrase Inhibitor
CTNNB1 I35N Tankyrase Inhibitor
CTNNB1 G38P Tankyrase Inhibitor
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
IWR-1 IWR-1 8 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
IWR-1 Tankyrase Inhibitor 9 IWR-1 selectively inhibits Wnt/beta-catenin mediated signaling by inhibiting tankyrase1/2, thus stabilizing Axin and stimulating beta-catenin degradation (PMID: 23621985).
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