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  • 1
    Online Resource
    Online Resource
    The GTPase KRAS suppresses the p53 tumor suppressor by activating the NRF2-regulated antioxidant defense system in cancer cells
    Elsevier BV ; 2020
    In:  Journal of Biological Chemistry Vol. 295, No. 10 ( 2020-03), p. 3055-3063
    Details
    In: Journal of Biological Chemistry, Elsevier BV, Vol. 295, No. 10 ( 2020-03), p. 3055-3063
    Type of Medium: Online Resource
    ISSN: 0021-9258
    URL: Article
    DOI: 10.1074/jbc.RA119.011930
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
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    detail.hit.zdb_id: 1474604-9
    SSG: 12
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  • 2
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    Online Resource
    Abstract 1750: Combined blockade of Aurora A and JAK2 kinase is highly effective at inhibiting malignant transformation
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 1750-1750
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 1750-1750
    Abstract: Our ongoing efforts to validate kinases for cancer therapy led to the novel finding that ectopic expression of JAK2 and Aurora A together is more effective than each alone at inducing normal cells to grow in an anchorage-independent manner and to invade. In addition, siRNA silencing or pharmacological inhibition of JAK2 and Aurora A with Ruxolitinib and Alisertib, respectively, is more effective than blocking each kinase alone at suppressing anchorage-dependent and -independent growth and invasion as well as at inducing apoptosis. This led us to develop dual Aurora and JAK inhibitors, AJI-214 and AJI-100, which potently inhibit the activities of Aurora A, Aurora B and JAK2 in vitro. In human cancer cells, these dual inhibitors block the auto-phosphorylation of Aurora A (Thr-288) and the phosphorylation of the Aurora B substrate histone H3 (Ser-10) and the JAK2 substrate STAT3 (Tyr-705). Furthermore, AJI-214 and AJI-100 inhibit anchorage dependent and independent cell growth and invasion and induce G2/M cell cycle accumulation and apoptosis. Finally, the more soluble AJI-100 was effective at inducing tumor regression of human xenografts in mice. Taken together, our genetic and pharmacological studies indicate that targeting Aurora A and JAK2 together is a more effective approach than each alone at inhibiting malignant transformation and warrant further advanced pre clinical investigations of dual Aurora A/JAK2 inhibitors as potential anti tumor agents. Citation Format: Said M. Sebti, Hua Yang, Harshani Lawrence, Aslamuzzaman Kazi, Harsukh Gervaria, Ronil Patel, Yunting Luo, Uwe Rix, Ernst Schonbrunn, Nicholas Lawrence. Combined blockade of Aurora A and JAK2 kinase is highly effective at inhibiting malignant transformation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1750. doi:10.1158/1538-7445.AM2014-1750
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-1750
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 3
    Online Resource
    Online Resource
    Dual Farnesyl and Geranylgeranyl Transferase Inhibitor Thwarts Mutant KRAS-Driven Patient-Derived Pancreatic Tumors
    American Association for Cancer Research (AACR) ; 2019
    In:  Clinical Cancer Research Vol. 25, No. 19 ( 2019-10-01), p. 5984-5996
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 25, No. 19 ( 2019-10-01), p. 5984-5996
    Abstract: Mutant KRAS is a major driver of pancreatic oncogenesis and therapy resistance, yet KRAS inhibitors are lacking in the clinic. KRAS requires farnesylation for membrane localization and cancer-causing activity prompting the development of farnesyltransferase inhibitors (FTIs) as anticancer agents. However, KRAS becomes geranylgeranylated and active when cancer cells are treated with FTIs. To overcome this geranylgeranylation-dependent resistance to FTIs, we designed FGTI-2734, a RAS C-terminal mimetic dual FT and geranylgeranyltransferase-1 inhibitor (GGTI). Experimental Design: Immunofluorescence, cellular fractionation, and gel shift assays were used to assess RAS membrane association, Western blotting to evaluate FGTI-2734 effects on signaling, and mouse models to demonstrate its antitumor activity. Results: FGTI-2734, but not the selective FTI-2148 and GGTI-2418, inhibited membrane localization of KRAS in pancreatic, lung, and colon human cancer cells. FGTI-2734 induced apoptosis and inhibited the growth in mice of mutant KRAS–dependent but not mutant KRAS–independent human tumors. Importantly, FGTI-2734 inhibited the growth of xenografts derived from four patients with pancreatic cancer with mutant KRAS (2 G12D and 2 G12V) tumors. FGTI-2734 was also highly effective at inhibiting, in three-dimensional cocultures with resistance promoting pancreatic stellate cells, the viability of primary and metastatic mutant KRAS tumor cells derived from eight patients with pancreatic cancer. Finally, FGTI-2734 suppressed oncogenic pathways mediated by AKT, mTOR, and cMYC while upregulating p53 and inducing apoptosis in patient-derived xenografts in vivo. Conclusions: The development of this novel dual FGTI overcomes a major hurdle in KRAS resistance, thwarting growth of patient-derived mutant KRAS–driven xenografts from patients with pancreatic cancer, and as such it warrants further preclinical and clinical studies.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-18-3399
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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    detail.hit.zdb_id: 2036787-9
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  • 4
    Online Resource
    Online Resource
    Global Phosphoproteomics Reveal CDK Suppression as a Vulnerability to KRas Addiction in Pancreatic Cancer
    American Association for Cancer Research (AACR) ; 2021
    In:  Clinical Cancer Research Vol. 27, No. 14 ( 2021-07-15), p. 4012-4024
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 27, No. 14 ( 2021-07-15), p. 4012-4024
    Abstract: Among human cancers that harbor mutant (mt) KRas, some, but not all, are dependent on mt KRas. However, little is known about what drives KRas dependency. Experimental Design: Global phosphoproteomics, screening of a chemical library of FDA drugs, and genome-wide CRISPR/Cas9 viability database analysis were used to identify vulnerabilities of KRas dependency. Results: Global phosphoproteomics revealed that KRas dependency is driven by a cyclin-dependent kinase (CDK) network. CRISPR/Cas9 viability database analysis revealed that, in mt KRas-driven pancreatic cancer cells, knocking out the cell-cycle regulators CDK1 or CDK2 or the transcriptional regulators CDK7 or CDK9 was as effective as knocking out KRas. Furthermore, screening of a library of FDA drugs identified AT7519, a CDK1, 2, 7, and 9 inhibitor, as a potent inducer of apoptosis in mt KRas-dependent, but not in mt KRas-independent, human cancer cells. In vivo AT7519 inhibited the phosphorylation of CDK1, 2, 7, and 9 substrates and suppressed growth of xenografts from 5 patients with pancreatic cancer. AT7519 also abrogated mt KRas and mt p53 primary and metastatic pancreatic cancer in three-dimensional (3D) organoids from 2 patients, 3D cocultures from 8 patients, and mouse 3D organoids from pancreatic intraepithelial neoplasia, primary, and metastatic tumors. Conclusions: A link between CDK hyperactivation and mt KRas dependency was uncovered and pharmacologically exploited to abrogate mt KRas-driven pancreatic cancer in highly relevant models, warranting clinical investigations of AT7519 in patients with pancreatic cancer.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-20-4781
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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    detail.hit.zdb_id: 2036787-9
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  • 5
    Online Resource
    Online Resource
    GSK3 suppression upregulates β-catenin and c-Myc to abrogate KRas-dependent tumors
    Springer Science and Business Media LLC ; 2018
    In:  Nature Communications Vol. 9, No. 1 ( 2018-12-04)
    Details
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 9, No. 1 ( 2018-12-04)
    Abstract: Mutant KRas is a significant driver of human oncogenesis and confers resistance to therapy, underscoring the need to develop approaches that disable mutant KRas-driven tumors. Because targeting KRas directly has proven difficult, identifying vulnerabilities specific for mutant KRas tumors is an important alternative approach. Here we show that glycogen synthase kinase 3 (GSK3) is required for the in vitro and in vivo growth and survival of human mutant KRas-dependent tumors but is dispensable for mutant KRas-independent tumors. Further, inhibiting phosphorylation of GSK3 substrates c-Myc on T58 and β-catenin on S33/S37/T41 and their subsequent upregulation contribute to the antitumor activity of GSK3 inhibition. Importantly, GSK3 blockade inhibits the in vivo growth of G12D, G12V, and G12C mutant KRas primary and metastatic patient-derived xenografts from pancreatic cancer patients who progressed on chemo- and radiation therapies. This discovery opens new avenues to target mutant KRas-dependent cancers.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/s41467-018-07644-6
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
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  • 6
    Online Resource
    Online Resource
    Abstract 1310: Abrogation of KRas-addicted tumors by GSK3 suppression-mediated upregulation of β-catenin and c-myc
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 1310-1310
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 1310-1310
    Abstract: The significant involvement of mutant KRas in human cancer development underscores the need to develop approaches that disable mutant KRas-driven tumors. Targeting KRas directly is challenging, and such identifying vulnerabilities specific for mutant KRas tumors is an important alternative approach. In this study, we discovered that glycogen synthase kinase 3 (GSK3) is required for the in vitro and in vivo growth and survival of human mutant KRas-dependent tumors but not for mutant KRas-independent tumors. Pharmacological inhibition with the GSK3 inhibitor SB as well as siRNA depletion of GSK3 lead to tumor suppression that is mediated at least in part by inhibition of the phosphorylation of the GSK3 substrates c-Myc on T58 and β-catenin on S33/S37/T41. CRISPR/Cas9 targeted knock out studies demonstrated that c-Myc and β-catenin upregulation mediate the antitumor activity of SB. Importantly, GSK3 blockade inhibits the in vivo growth of G12D, G12V, and G12C mutant KRas primary and metastatic patient-derived xenografts from pancreatic cancer patients who progressed on chemo- and radiation therapies. This discovery warrants advanced pre-clinical and clinical investigations of GSK3 inhibitors in mutant KRas-dependent cancers. Note: This abstract was not presented at the meeting. Citation Format: Aslamuzzaman Kazi, Shengyan Xiang, Hua Yang, Daniel Delitto, Jose Trevino, Rays H. Jiang, Muhammad Ayaz, Harshani Lawrence, Perry Kennedy, Said M. Sebti. Abrogation of KRas-addicted tumors by GSK3 suppression-mediated upregulation of β-catenin and c-myc [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1310.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-1310
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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    detail.hit.zdb_id: 410466-3
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  • 7
    Online Resource
    Online Resource
    Abstract 3088: Farnesyl/geranylgeranyl transferase dual inhibitor thwarts mutant KRas-driven patient-derived pancreatic tumors
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 3088-3088
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 3088-3088
    Abstract: Although mutant KRas is a significant driver of pancreatic oncogenesis and resistance to therapy, there are no KRas inhibitors available for these patients. Farnesyltransferase inhibitors (FTIs) were developed as potential anticancer drugs because KRas requires farnesylation for its membrane localization and cancer-causing activity. However, KRas becomes geranylgeranylated and active when cancer cells are treated with FTIs. In this study, we designed a Ras C-terminal mimetic dual Farnesyl/geranylgeranyltransferase-1 (GGT-1) inhibitor, FGTI-2734, to overcome the geranylgeranylation-dependent resistance to FTIs. Immunofluorescence, cellular fractionation, and gel shift assays showed that FGTI-2734, but not the selective FTI-2148 and GGTI-2418, inhibited membrane localization of KRas in mt KRas pancreatic, lung, and colon human cancer cells. FGTI-2734 inhibited the growth in mice of mt KRas-dependent but not -independent human tumors, indicating its selectivity for mt KRas-driven cancers. Importantly, FGTI-2734 inhibited the in vivo growth of xenografts derived from four pancreatic cancer patients with mt KRas (two G12D, and two G12V) tumors. In addition, FGTI-2734 was highly effective at inhibiting, in three-dimensional co-cultures with chemotherapy resistance-promoting pancreatic stellate cells, the viability of primary and metastatic mutant KRas (G12D, G13D, and G12V) tumor cells derived from 8 pancreatic cancer patients. Finally, FGTI-2734 suppressed oncogenic pathways mediated by Akt, mTOR, and cMyc while upregulating p53 and inducing apoptosis in patient-derived xenografts in vivo. Thus, the development of this novel dual FT and GGT-1 inhibitor overcomes a major hurdle in KRas resistance, thwarting the growth of patient-derived mutant KRas-driven xenografts from pancreatic cancer patients, and as such it warrants further advanced preclinical and clinical studies. Citation Format: Aslamuzzaman Kazi, Shengyan Xiang, Hua Yang, Liwei Chen, Perry Kennedy, Muhammad Ayaz, Steven Fletcher, Christopher Cummings, Harshani Lawrence, Francisca Beato, Ya'an Yang, Michael P. Kim, Andrea Delitto, Patrick Underwood, Jason B. Fleming, Jose Trevino, Andrew D. Hamilton, Said M. Sebti. Farnesyl/geranylgeranyl transferase dual inhibitor thwarts mutant KRas-driven patient-derived pancreatic tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3088.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-3088
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 8
    Online Resource
    Online Resource
    Dual Aurora A and JAK2 kinase blockade effectively suppresses malignant transformation
    Impact Journals, LLC ; 2014
    In:  Oncotarget Vol. 5, No. 10 ( 2014-05-30), p. 2947-2961
    Details
    In: Oncotarget, Impact Journals, LLC, Vol. 5, No. 10 ( 2014-05-30), p. 2947-2961
    Type of Medium: Online Resource
    ISSN: 1949-2553
    URL: Issue
    URL: Article
    DOI: 10.18632/oncotarget.v5i10
    DOI: 10.18632/oncotarget.1615
    Language: English
    Publisher: Impact Journals, LLC
    Publication Date: 2014
    detail.hit.zdb_id: 2560162-3
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