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  • 1
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    Abstract A212: Preclinical efficacy of MEK inhibition in a K-Ras driven cholangiocarcinoma preclinical model
    American Association for Cancer Research (AACR) ; 2018
    In:  Molecular Cancer Therapeutics Vol. 17, No. 1_Supplement ( 2018-01-01), p. A212-A212
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 17, No. 1_Supplement ( 2018-01-01), p. A212-A212
    Abstract: Intrahepatic cholangiocarcinoma (iCCA) is a form of deadly malignancy with limited treatment options. Gain-of-function mutations in KRAS are one of the most frequent mutations, found in ~25% of human CCA patients. MEK inhibitors have been developed and show some activity against solid tumors with Ras mutants. However, whether MEK inhibitors are effective against KRas mutant CCAs remains unknown. In the current study, we established a new mouse iCCA model (NICD/KRas) by expressing activated forms of Notch (NICD) and KRas (KRasV12D). We investigated the therapeutic potential of MEK inhibitors in vitro using human CCA cell lines and in vivo using KRasV12/NICD iCCA preclinical model. We found that in general, CCA cell lines with KRas mutations are more sensitive to MEK inhibitor U0126. Treatment of U0126 in KRas mutant CCA cells leads to increased apoptosis and decreased expression of pro-apoptosis gene Survivin. Furthermore, we found that treating KRasV12/NICD tumor-bearing mice with MEK inhibitor PD0325901 (PD901) resulted in stable disease. At molecular levels, PD901 efficiently inhibited p-ERK expression KRasV12/NICD tumor cells, leading to increased apoptosis. In summary, our studies demonstrate that KRasV12/NICD mice represent a novel and useful preclinical model to study KRas-driven CCA development. Our data further support the usefulness of MEK inhibitors for treatment of KRas mutant CCA in patients. Citation Format: Mingjie Dong, Xianqiong Liu, Katja Evert, Kirsten Utpatel, Shanshan Zhang, Li Che, John Gordan, Diego Calvisi, Matthias evert, Yan Liu, Xin Chen. Preclinical efficacy of MEK inhibition in a K-Ras driven cholangiocarcinoma preclinical model [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A212.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-17-A212
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2062135-8
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  • 2
    Online Resource
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    Efficacy of MEK inhibition in a K-Ras-driven cholangiocarcinoma preclinical model
    Springer Science and Business Media LLC ; 2018
    In:  Cell Death & Disease Vol. 9, No. 2 ( 2018-01-18)
    Details
    In: Cell Death & Disease, Springer Science and Business Media LLC, Vol. 9, No. 2 ( 2018-01-18)
    Abstract: Intrahepatic cholangiocarcinoma (iCCA) is a deadly malignancy with limited treatment options. Gain-of-function mutations in K-Ras is a very frequent alteration, occurring in ~15 to 25% of human iCCA patients. Here, we established a new iCCA model by expressing activated forms of Notch1 (NICD) and K-Ras (K-Ras V12D ) in the mouse liver (K-Ras/NICD mice). Furthermore, we investigated the therapeutic potential of MEK inhibitors in vitro and in vivo using human CCA cell lines and K-Ras/NICD mice, respectively. Treatment with U0126, PD901, and Selumetinib MEK inhibitors triggered growth restraint in all CCA cell lines tested, with the most pronounced growth suppressive effects being observed in K-Ras mutant cells. Growth inhibition was due to reduction in proliferation and massive apoptosis. Furthermore, treatment of K-Ras/NICD tumor-bearing mice with PD901 resulted in stable disease. At the molecular level, PD901 efficiently inhibited ERK activation in K-Ras/NICD tumor cells, mainly leading to increased apoptosis. Altogether, our study demonstrates that K-Ras/NICD mice represent a novel and useful preclinical model to study K-Ras-driven iCCA development and the effectiveness of MEK inhibitors in counteracting this process. Our data support the usefulness of MEK inhibitors for the treatment of human iCCA.
    Type of Medium: Online Resource
    ISSN: 2041-4889
    URL: Article
    DOI: 10.1038/s41419-017-0183-4
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
    detail.hit.zdb_id: 2541626-1
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  • 3
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    Pan-mTOR inhibitor MLN0128 is effective against intrahepatic cholangiocarcinoma in mice
    Elsevier BV ; 2017
    In:  Journal of Hepatology Vol. 67, No. 6 ( 2017-12), p. 1194-1203
    Details
    In: Journal of Hepatology, Elsevier BV, Vol. 67, No. 6 ( 2017-12), p. 1194-1203
    Type of Medium: Online Resource
    ISSN: 0168-8278
    URL: Article
    DOI: 10.1016/j.jhep.2017.07.006
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2017
    detail.hit.zdb_id: 2027112-8
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  • 4
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    Axis inhibition protein 1 (Axin1) Deletion–Induced Hepatocarcinogenesis Requires Intact β‐Catenin but Not Notch Cascade in Mice
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Hepatology Vol. 70, No. 6 ( 2019-12), p. 2003-2017
    Details
    In: Hepatology, Ovid Technologies (Wolters Kluwer Health), Vol. 70, No. 6 ( 2019-12), p. 2003-2017
    Abstract: Inactivating mutations of axis inhibition protein 1 ( AXIN1 ), a negative regulator of the Wnt/β‐Catenin cascade, are among the common genetic events in human hepatocellular carcinoma (HCC), affecting approximately 10% of cases. In the present manuscript, we sought to define the genetic crosstalk between Axin1 mutants and Wnt/β‐catenin as well as Notch signaling cascades along hepatocarcinogenesis. We discovered that c‐MET activation and AXIN1 mutations occur concomitantly in ~3%‐5% of human HCC samples. Subsequently, we generated a murine HCC model by means of CRISPR/Cas9‐based gene deletion of Axin1 (sgAxin1) in combination with transposon‐based expression of c‐Met in the mouse liver (c‐Met/sgAxin1). Global gene expression analysis of mouse normal liver, HCCs induced by c‐Met/sgAxin1, and HCCs induced by c‐Met/∆N90‐β‐Catenin revealed activation of the Wnt/β‐Catenin and Notch signaling in c‐Met/sgAxin1 HCCs. However, only a few of the canonical Wnt/β‐Catenin target genes were induced in c‐Met/sgAxin1 HCC when compared with corresponding lesions from c‐Met/∆N90‐β‐Catenin mice. To study whether endogenous β‐Catenin is required for c‐Met/sgAxin1‐driven HCC development, we expressed c‐Met/sgAxin1 in liver‐specific Ctnnb1 null mice, which completely prevented HCC development. Consistently, in AXIN1 mutant or null human HCC cell lines, silencing of β‐Catenin strongly inhibited cell proliferation. In striking contrast, blocking the Notch cascade through expression of either the dominant negative form of the recombinant signal‐binding protein for immunoglobulin kappa J region (RBP‐J) or the ablation of Notch2 did not significantly affect c‐Met/sgAxin1‐driven hepatocarcinogenesis. Conclusion: We demonstrated here that loss of Axin1 cooperates with c‐Met to induce HCC in mice, in a β‐Catenin signaling–dependent but Notch cascade–independent way.
    Type of Medium: Online Resource
    ISSN: 0270-9139 , 1527-3350
    URL: Article
    DOI: 10.1002/hep.30556
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
    detail.hit.zdb_id: 1472120-X
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  • 5
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    The mTORC2‐Akt1 Cascade Is Crucial for c‐Myc to Promote Hepatocarcinogenesis in Mice and Humans
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Hepatology Vol. 70, No. 5 ( 2019-11), p. 1600-1613
    Details
    In: Hepatology, Ovid Technologies (Wolters Kluwer Health), Vol. 70, No. 5 ( 2019-11), p. 1600-1613
    Abstract: Hepatocellular carcinoma (HCC) is a deadly form of liver cancer with limited treatment options. The c‐Myc transcription factor is a pivotal player in hepatocarcinogenesis, but the mechanisms underlying c‐Myc oncogenic activity in the liver remain poorly delineated. Mammalian target of rapamycin complex 2 (mTORC2) has been implicated in cancer by regulating multiple AGC kinases, especially AKT proteins. In the liver, AKT1 and AKT2 are widely expressed. While AKT2 is the major isoform downstream of activated phosphoinositide 3‐kinase and loss of phosphatase and tensin homolog–induced HCC, the precise function of AKT1 in hepatocarcinogenesis is largely unknown. In the present study, we demonstrate that mTORC2 is activated in c‐Myc‐driven mouse HCC, leading to phosphorylation/activation of Akt1 but not Akt2. Ablation of Rictor inhibited c‐Myc‐induced HCC formation in vivo . Mechanistically, we discovered that loss of Akt1 , but not Akt2 , completely prevented c‐Myc HCC formation in mice. Silencing of Rictor or Akt1 in c‐Myc HCC cell lines inhibited phosphorylated forkhead box o1 expression and strongly suppressed cell growth in vitro . In human HCC samples, c‐MYC activation is strongly correlated with phosphorylated AKT1 expression. Higher expression of RICTOR and AKT1, but not AKT2, is associated with poor survival of patients with HCC. In c‐Myc mice, while rapamycin, an mTORC1 inhibitor, had limited efficacy at preventing c‐Myc‐driven HCC progression, the dual mTORC1 and mTORC2 inhibitor MLN0128 effectively promoted tumor regression by inducing apoptosis and necrosis. Conclusion: Our study indicates the functional contribution of mTORC2/Akt1 along c‐Myc‐induced hepatocarcinogenesis, with AKT1 and AKT2 having distinct roles in HCC development and progression; targeting both mTORC1 and mTORC2 may be required for effective treatment of human HCC displaying c‐Myc amplification or overexpression.
    Type of Medium: Online Resource
    ISSN: 0270-9139 , 1527-3350
    URL: Article
    DOI: 10.1002/hep.30697
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
    detail.hit.zdb_id: 1472120-X
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  • 6
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    Cholesterol biosynthesis supports the growth of hepatocarcinoma lesions depleted of fatty acid synthase in mice and humans
    BMJ ; 2020
    In:  Gut Vol. 69, No. 1 ( 2020-01), p. 177-186
    Details
    In: Gut, BMJ, Vol. 69, No. 1 ( 2020-01), p. 177-186
    Abstract: Increased de novo fatty acid (FA) synthesis and cholesterol biosynthesis have been independently described in many tumour types, including hepatocellular carcinoma (HCC). Design We investigated the functional contribution of fatty acid synthase (Fasn)-mediated de novo FA synthesis in a murine HCC model induced by loss of Pten and overexpression of c-Met (sgPten/c-Met) using liver-specific Fasn knockout mice. Expression arrays and lipidomic analysis were performed to characterise the global gene expression and lipid profiles, respectively, of sgPten/c-Met HCC from wild-type and Fasn knockout mice. Human HCC cell lines were used for in vitro studies. Results Ablation of Fasn significantly delayed sgPten/c-Met-driven hepatocarcinogenesis in mice. However, eventually, HCC emerged in Fasn knockout mice. Comparative genomic and lipidomic analyses revealed the upregulation of genes involved in cholesterol biosynthesis, as well as decreased triglyceride levels and increased cholesterol esters, in HCC from these mice. Mechanistically, loss of Fasn promoted nuclear localisation and activation of sterol regulatory element binding protein 2 (Srebp2), which triggered cholesterogenesis. Blocking cholesterol synthesis via the dominant negative form of Srebp2 ( dnSrebp2 ) completely prevented sgPten/c-Met-driven hepatocarcinogenesis in Fasn knockout mice. Similarly, silencing of FASN resulted in increased SREBP2 activation and hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase ( HMGCR) expression in human HCC cell lines. Concomitant inhibition of FASN-mediated FA synthesis and HMGCR-driven cholesterol production was highly detrimental for HCC cell growth in culture. Conclusion Our study uncovers a novel functional crosstalk between aberrant lipogenesis and cholesterol biosynthesis pathways in hepatocarcinogenesis, whose concomitant inhibition might represent a therapeutic option for HCC.
    Type of Medium: Online Resource
    ISSN: 0017-5749 , 1468-3288
    URL: Article
    DOI: 10.1136/gutjnl-2018-317581
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2020
    detail.hit.zdb_id: 1492637-4
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  • 7
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    Activated mutant forms of PIK 3 CA cooperate with RasV12 or c‐Met to induce liver tumour formation in mice via AKT 2/ mTORC 1 cascade
    Wiley ; 2016
    In:  Liver International Vol. 36, No. 8 ( 2016-08), p. 1176-1186
    Details
    In: Liver International, Wiley, Vol. 36, No. 8 ( 2016-08), p. 1176-1186
    Abstract: Activating mutations of PIK 3 CA occur in various tumour types, including human hepatocellular carcinoma. The mechanisms whereby PIK 3 CA contributes to hepatocarcinogenesis remain poorly understood. Methods PIK 3 CA mutants H1047R or E545K were hydrodynamically transfected, either alone or in combination with NR asV12 or c‐Met genes, in the mouse liver. Results Overexpression of H1047R or E545K alone was able to induce AKT / mTOR signalling in the mouse liver, leading to hepatic steatosis. However, none of the mice developed liver tumours over long term. In contrast, H1047R or E545K cooperated with NR asV12 or c‐Met to rapidly induce liver tumour formation in mice. At the molecular level, all the tumour nodules displayed activation of AKT / mTOR and Ras/ MAPK cascades. Ablation of AKT 2 significantly inhibited hepatic steatosis induced by H1047R or E545K and carcinogenesis induced by H1047R/c‐Met or E545K/c‐Met. Furthermore, tumourigenesis induced by H1047R/c‐Met was abolished in conditional Raptor knockout mice. Conclusions Both H1047R and E545K are able to activate the AKT / mTOR pathway. An intact AKT 2/ mTOR complex 1 cascade is required for tumourigenesis induced by H1047R/c‐Met or E545K/c‐Met in the liver.
    Type of Medium: Online Resource
    ISSN: 1478-3223 , 1478-3231
    URL: Issue
    URL: Article
    DOI: 10.1111/liv.2016.36.issue-8
    DOI: 10.1111/liv.13055
    Language: English
    Publisher: Wiley
    Publication Date: 2016
    detail.hit.zdb_id: 2124684-1
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  • 8
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    Focal adhesion kinase (FAK) promotes cholangiocarcinoma development and progression via YAP activation
    Elsevier BV ; 2021
    In:  Journal of Hepatology Vol. 75, No. 4 ( 2021-10), p. 888-899
    Details
    In: Journal of Hepatology, Elsevier BV, Vol. 75, No. 4 ( 2021-10), p. 888-899
    Type of Medium: Online Resource
    ISSN: 0168-8278
    URL: Article
    DOI: 10.1016/j.jhep.2021.05.018
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
    detail.hit.zdb_id: 2027112-8
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  • 9
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    Combined CDK4/6 and Pan-mTOR Inhibition Is Synergistic Against Intrahepatic Cholangiocarcinoma
    American Association for Cancer Research (AACR) ; 2019
    In:  Clinical Cancer Research Vol. 25, No. 1 ( 2019-01-01), p. 403-413
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 25, No. 1 ( 2019-01-01), p. 403-413
    Abstract: Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer type, lacking effective therapies and associated with a dismal prognosis. Palbociclib is a selective CDK4/6 inhibitor, which has been shown to suppress cell proliferation in many experimental cancer models. Recently, we demonstrated that pan-mTOR inhibitors, such as MLN0128, effectively induce apoptosis, although have limited efficacy in restraining proliferation of ICC cells. Here, we tested the hypothesis that palbociclib, due to its antproliferative properties in many cancer types, might synergize with MLN0128 to impair ICC growth. Experimental Design: Human ICC cell lines and the AKT/YapS127A ICC mouse model were used to test the therapeutic efficacy of palbociclib and MLN0128, either alone or in combination. Results: Administration of palbociclib suppressed in vitro ICC cell growth by inhibiting cell-cycle progression. Concomitant administration of palbociclib and MLN0128 led to a pronounced, synergistic growth constraint of ICC cell lines. Furthermore, while treatment with palbociclib or MLN0128 alone resulted in tumor growth reduction in AKT/YapS127A mice, a remarkable tumor regression was achieved when the two drugs were administered simultaneously. Mechanistically, palbociclib was found to potentiate MLN0128 mTOR inhibition activity, whereas MLN0128 prevented the upregulation of cyclin D1 induced by palbociclib treatment. Conclusions: Our study indicates the synergistic activity of palbociclib and MLN0128 in inhibiting ICC cell proliferation. Thus, combination of CDK4/6 and mTOR inhibitors might represent a novel, promising, and effective therapeutic approach against human ICC. See related commentary by Malumbres, p. 6
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-18-0284
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 10
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    Pivotal Role of Fatty Acid Synthase in c-MYC Driven Hepatocarcinogenesis
    MDPI AG ; 2020
    In:  International Journal of Molecular Sciences Vol. 21, No. 22 ( 2020-11-11), p. 8467-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 21, No. 22 ( 2020-11-11), p. 8467-
    Abstract: Hepatocellular carcinoma (HCC) is a deadly form of liver malignancy with limited treatment options. Amplification and/or overexpression of c-MYC is one of the most frequent genetic events in human HCC. The mammalian target of Rapamycin Complex 1 (mTORC1) is a major functional axis regulating various aspects of cellular growth and metabolism. Recently, we demonstrated that mTORC1 is necessary for c-Myc driven hepatocarcinogenesis as well as for HCC cell growth in vitro. Among the pivotal downstream effectors of mTORC1, upregulation of Fatty Acid Synthase (FASN) and its mediated de novo lipogenesis is a hallmark of human HCC. Here, we investigated the importance of FASN on c-Myc-dependent hepatocarcinogenesis using in vitro and in vivo approaches. In mouse and human HCC cells, we found that FASN suppression by either gene silencing or soluble inhibitors more effectively suppressed proliferation and induced apoptosis in the presence of high c-MYC expression. In c-Myc/Myeloid cell leukemia 1 (MCL1) mouse liver tumor lesions, FASN expression was markedly upregulated. Most importantly, genetic ablation of Fasn profoundly delayed (without abolishing) c-Myc/MCL1 induced HCC formation. Liver tumors developing in c-Myc/MCL1 mice depleted of Fasn showed a reduction in proliferation and an increase in apoptosis when compared with corresponding lesions from c-Myc/MCL1 mice with an intact Fasn gene. In human HCC samples, a significant correlation between the levels of c-MYC transcriptional activity and the expression of FASN mRNA was detected. Altogether, our study indicates that FASN is an important effector downstream of mTORC1 in c-MYC induced HCC. Targeting FASN may be helpful for the treatment of human HCC, at least in the tumor subset displaying c-MYC amplification or activation.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms21228467
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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