Tankyrase Inhibitor Sensitizes Lung Cancer Cells to Endothelial Growth Factor Receptor (EGFR) Inhibition via Stabilizing Angiomotins and Inhibiting YAP Signaling

Wang, Hui; Lü, Bo; Castillo-Cabrera, Johnny; Zhang, Yue; Yang, Zinger; McAllister, Gregory; Lindeman, Alicia; Reece‐Hoyes, John S.; Tallarico, John A.; Russ, Carsten; Hoffman, Greg; Xu, Wenqing; Schirle, Markus; Cong, Feng

doi:10.1074/jbc.m116.722967

Cited by 67 publications

(71 citation statements)

References 52 publications

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“…67 In addition, tankyrase has recently been reported to allow cancer cells to survive against EGFR TKI through the Hippo/yes-associated protein pathway. 68 A tankyrase inhibitor, AZ1366, showed synergistic efficacy with gefitinib in H3255, H1650, HCC4006, and HCC4011 cells but not in HCC827 and PC9 cells. 69 …”

Section: Reversible Drug-tolerant Statementioning

confidence: 95%

Primary Double-Strike Therapy for Cancers to Overcome EGFR Kinase Inhibitor Resistance: Proposal from the Bench

Suda

Bunn

Rivard

et al. 2017

Journal of Thoracic Oncology

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Diverse molecular mechanisms that confer acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in lung cancers with sensitive EGFR mutations have been reported. However, it is not realistic to analyze for all these mechanisms at the time of resistance in clinical practice and establish adequate treatment targeting these numerous resistance mechanisms. Therefore, we believe that we should move our research focus from the exploration of “established” diverse resistance mechanisms to the elucidation of molecular mechanisms that enable cancer cells to remain alive at the early phase of the treatment. Here in this review, we summarize up-to-date molecular mechanisms that maintain residual tumor cells against EGFR TKI monotherapy in lung cancers with EGFR mutations. We classified these mechanisms into three categories. The first is a pre-existing minor subpopulation with a resistance mechanism such as a pretreatment T790M mutation that can be detected by highly sensitivity methods. The second is the reversible drug-tolerant state that is often observed in cell line models and accounts for the lack of complete response and continued survival of cells exposed to EGFR TKIs in patients. And the last is the role of the microenvironment, including survival signaling from fibroblasts or dying cancer cells and the role of poor vascularization. Primary double-strike cancer therapy, or even initial multiple-strike therapy, to cancer cells that cotarget EGFR and survival mechanism(s) simultaneously would be a promising strategy to improve the outcomes of patients with EGFR mutations.

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Section: Reversible Drug-tolerant Statementioning

confidence: 95%

Primary Double-Strike Therapy for Cancers to Overcome EGFR Kinase Inhibitor Resistance: Proposal from the Bench

Suda

Bunn

Rivard

et al. 2017

Journal of Thoracic Oncology

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“…There have been a number of reports that TNKSs can regulate the cellular concentrations of several proteins including TRF1, 3BP2, Axin‐1/2, BLF1, CASC3, CPAP, PTEN, and, most recently, the angiomotin (AMOT) family of proteins, in a PARylation‐dependent manner. The PARylated forms of BLF1, CASC3, the disease related proteins PTEN, Axin, 3BP2, and the angiomotins are confirmed substrates of RNF146 [whose domain architecture is shown in Fig.…”

Section: Introductionmentioning

confidence: 99%

“…The PARylated forms of BLF1, CASC3, the disease related proteins PTEN, Axin, 3BP2, and the angiomotins are confirmed substrates of RNF146 [whose domain architecture is shown in Fig. (B)], which targets these proteins for degradation by attachment of poly‐ubiquitin chains …”

Section: Introductionmentioning

confidence: 99%

“…6,7 The tankryases (TNKSs or simply tankyrase) have particularly key roles in cell growth, division, and differentiation. [8][9][10][11][12][13][14][15][16][17] As regulators of multiple signal transduction pathways including Wnt, Src, and Hippo signaling, tankyrases have emerged as important drug targets for cancer therapies. [18][19][20] Other than sharing a PARP catalytic domain at its extreme C-terminus, the TNKS proteins have a unique domain composition when compared to other PARP enzymes [ Fig.…”

Section: Introductionmentioning

confidence: 99%

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Structural basis for tankyrase‐RNF146 interaction reveals noncanonical tankyrase‐binding motifs

DaRosa¹,

Klevit²,

Xu³

2018

Protein Science

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Poly(ADP-ribosyl)ation (PARylation) catalyzed by the tankyrase enzymes (Tankyrase-1 and -2; a.k.a. PARP-5a and -5b) is involved in mitosis, telomere length regulation, GLUT-4 vesicle transport, and cell growth and differentiation. Together with the E3 ubiquitin ligase RNF146 (a.k.a. Iduna), tankyrases regulate the cellular levels of several important proteins including Axin, 3BP2, and angiomotins, which are key regulators of Wnt, Src and Hippo signaling, respectively. These tankyrase substrates are first PARylated and then ubiquitylated by RNF146, which is allosterically activated by binding to PAR polymer. Each tankyrase substrate is recognized by a tankyrase-binding motif (TBM). Here we show that RNF146 binds directly to tankyrases via motifs in its C-terminal region. Four of these RNF146 motifs represent novel, extended TBMs, that have one or two additional amino acids between the most conserved Arg and Gly residues. The individual RNF146 motifs display weak binding, but together mediate a strong multivalent interaction with the substrate-binding region of TNKS, forming a robust one-to-one complex. A crystal structure of the first RNF146 noncanonical TBM in complex with the second ankyrin repeat domain of TNKS shows how an extended motif can be accommodated in a peptide-binding groove on tankyrases. Overall, our work demonstrates the existence of a new class of extended TBMs that exist in previously uncharacterized tankyrase-binding proteins including those of IF4A1 and NELFE.

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“…Altered levels of TNKSs expression have been reported in lung cancer (Wang et al, 2016), breast cancer (Gelmini et al, 2004), gastric cancer (Gao et al, 2011), bladder cancer (Gelmini et al, 2007), brain tumors (La Torre et al, 2013), colon carcinoma (Waaler et al, 2012) and pancreatic adenocarcinoma (Lehtiö et al, 2013). TNKSs inhibitors were classified into three main groups (Liscio et al, 2014);i) compounds that bind to nicotinamide subside and working as nicotinamide isosteres (Wahlberg et al, 2012) such as lactam-based pyrimidin-4-one (XAV939) (Huang et al, 2009) and non-lactam inhibitors (Shultz et al, 2013), ii) compounds that bind to adjacent induced pocket of the enzymes, adenoside sub-site, (Gunaydin and Huang, 2012;Bregman et al, 2013) and iii) dual binder compounds that simultaneously occupy both sites aforementioned (Hua et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Accessing the Anti-Proliferating Activity of Tankyrase-2 Inhibitors via 2D, 3D-QSAR and Molecular Docking: Assessment of Structure Activity Relationships

2017

J App Pharm Sci

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Tankyrases (TNKSs) have been implicated in many biological processes and have been proposed as a drug target for cancer therapy. The human genome encodes two homologous isoforms, TNKS-1 and TNKS-2. This study reported the first theoretical study of three-dimensional, two-dimensional quantitative structure activity relationships and a docking analysis of a series of 2-arylquinazolin-4-one, 3-arylisoquinolin-1-one, arylnaphthyridinone and aryltetrahydronaphthyridinone derivatives with remarkable TNKS-2 inhibiting activities reported recently in literatures. The predictive ability of the QSAR models was assessed using internal and external validation. 3D-QSAR model showed that the substituents R1 and R2 in studied compounds are key modulators to enhance the TNKS-2 inhibition. The 2D-QSAR model, was based mainly on three 2D descriptors and nine 3D descriptors. This suggested that TNKS-2 inhibition is predominantly controlled by steric properties of the inhibitors. Docking study was carried out by using ligands docking on the active site of three different crystal structures of TNKS-2 to understand the binding mode of these compounds as TNKS-2 inhibitors. We discussed the structural requirements for selective and potent TNKS-2 inhibitors. Four potent inhibitors were designed to be synthesized in the future.

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Tankyrase Inhibitor Sensitizes Lung Cancer Cells to Endothelial Growth Factor Receptor (EGFR) Inhibition via Stabilizing Angiomotins and Inhibiting YAP Signaling

Cited by 67 publications

References 52 publications

Primary Double-Strike Therapy for Cancers to Overcome EGFR Kinase Inhibitor Resistance: Proposal from the Bench

Primary Double-Strike Therapy for Cancers to Overcome EGFR Kinase Inhibitor Resistance: Proposal from the Bench

Structural basis for tankyrase‐RNF146 interaction reveals noncanonical tankyrase‐binding motifs

Accessing the Anti-Proliferating Activity of Tankyrase-2 Inhibitors via 2D, 3D-QSAR and Molecular Docking: Assessment of Structure Activity Relationships

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