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  • 1
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    Blockade of vascular endothelial growth factor receptors by tivozanib has potential anti-tumour effects on human glioblastoma cells
    Springer Science and Business Media LLC ; 2017
    In:  Scientific Reports Vol. 7, No. 1 ( 2017-03-13)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 7, No. 1 ( 2017-03-13)
    Abstract: Glioblastoma (GBM) remains one of the most fatal human malignancies due to its high angiogenic and infiltrative capacities. Even with optimal therapy including surgery, radiotherapy and temozolomide, it is essentially incurable. GBM is among the most neovascularised neoplasms and its malignant progression associates with striking neovascularisation, evidenced by vasoproliferation and endothelial cell hyperplasia. Targeting the pro-angiogenic pathways is therefore a promising anti-glioma strategy. Here we show that tivozanib, a pan-inhibitor of vascular endothelial growth factor (VEGF) receptors, inhibited proliferation of GBM cells through a G2/M cell cycle arrest via inhibition of polo-like kinase 1 (PLK1) signalling pathway and down-modulation of Aurora kinases A and B, cyclin B1 and CDC25C. Moreover, tivozanib decreased adhesive potential of these cells through reduction of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Tivozanib diminished GBM cell invasion through impairing the proteolytic cascade of cathepsin B/urokinase-type plasminogen activator (uPA)/matrix metalloproteinase-2 (MMP-2). Combination of tivozanib with EGFR small molecule inhibitor gefitinib synergistically increased sensitivity to gefitinib. Altogether, these findings suggest that VEGFR blockade by tivozanib has potential anti-glioma effects in vitro . Further in vivo studies are warranted to explore the anti-tumour activity of tivozanib in combinatorial approaches in GBM.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/srep44075
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2017
    detail.hit.zdb_id: 2615211-3
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  • 2
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    Tracking the Evolution of Resistance to ALK Tyrosine Kinase Inhibitors Through Longitudinal Analysis of Circulating Tumor DNA
    American Society of Clinical Oncology (ASCO) ; 2018
    In:  JCO Precision Oncology , No. 2 ( 2018-11), p. 1-14
    Details
    In: JCO Precision Oncology, American Society of Clinical Oncology (ASCO), , No. 2 ( 2018-11), p. 1-14
    Abstract: ALK (anaplastic lymphoma kinase) rearrangements predict for sensitivity to ALK tyrosine kinase inhibitors (TKIs); however, responses to ALK TKIs are generally short lived. Serial molecular analysis is an informative strategy used to identify genetic mediators of resistance. Although multiple studies support the clinical benefits of repeat tissue sampling, the clinical utility of longitudinal circulating tumor DNA analysis has not been established in ALK-positive lung cancer. Patients and Methods We used a 566-gene hybrid-capture next-generation sequencing assay to perform a longitudinal analysis of plasma specimens from 22 ALK-positive patients with acquired resistance to ALK TKIs to track the evolution of resistance during treatment. To determine tissue–plasma concordance, we compared plasma findings with the results of repeat biopsies. Results At disease progression, we detected an ALK fusion in plasma from 19 (86%) of 22 patients and identified ALK resistance mutations in plasma specimens from 11 patients (50%). There was 100% agreement between tissue- and plasma-detected ALK fusions. Among 16 patients for which contemporaneous plasma and tissue specimens were available, we observed 100% concordance between ALK mutation calls. ALK mutations emerged and disappeared during treatment with sequential ALK TKIs, which suggests that plasma mutation profiles were dependent on the specific TKI administered. ALK G1202R—the most frequent plasma mutation detected after progression on a second-generation TKI—was consistently suppressed during treatment with lorlatinib. Conclusion Plasma genotyping by next-generation sequencing is an effective method for detecting ALK fusions and ALK mutations in patients who experience disease progression on ALK TKIs. The correlation between plasma ALK mutations and the response to distinct ALK TKIs highlights the potential for plasma analysis to guide the selection of ALK-directed therapies.
    Type of Medium: Online Resource
    ISSN: 2473-4284
    URL: Article
    DOI: 10.1200/PO.17.00160
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
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  • 3
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    Patterns of Metastatic Spread and Mechanisms of Resistance to Crizotinib in ROS1 -Positive Non–Small-Cell Lung Cancer
    American Society of Clinical Oncology (ASCO) ; 2017
    In:  JCO Precision Oncology , No. 1 ( 2017-11), p. 1-13
    Details
    In: JCO Precision Oncology, American Society of Clinical Oncology (ASCO), , No. 1 ( 2017-11), p. 1-13
    Abstract: The ROS1 tyrosine kinase is activated through ROS1 gene rearrangements in 1% to 2% of non–small-cell lung cancers (NSCLCs), which confer sensitivity to treatment with the anaplastic lymphoma kinase (ALK)/ROS1/mesenchymal-epithelial transition factor inhibitor crizotinib. Currently, insights into patterns of metastatic spread and mechanisms of crizotinib resistance among patients with ROS1-positive disease are limited. Patients and Methods We reviewed clinical and radiographic imaging data of patients with ROS1- and ALK-positive NSCLC to compare patterns of metastatic spread at initial metastatic diagnosis. To determine molecular mechanisms of crizotinib resistance, we analyzed repeat biopsy specimens from a cohort of patients with ROS1-positive disease who progressed on crizotinib. Results We identified 39 and 196 patients with advanced ROS1- and ALK-positive NSCLC, respectively. Patients with ROS1-positive disease had significantly lower rates of extrathoracic metastases ( ROS1, 59.0%; ALK, 83.2%; P = .002), including lower rates of brain metastases ( ROS1, 19.4%; ALK, 39.1%; P = .033), at initial metastatic diagnosis. Despite similar overall survival between patients with ALK- and ROS1-positive NSCLC treated with crizotinib (median, 3.0 v 2.5 years, respectively; P = .786), patients with ROS1-positive NSCLC also had a significantly lower cumulative incidence of brain metastases (34% v 73% at 5 years; P 〈 .001). In addition, we identified 16 patients who underwent a total of 17 repeat biopsies after progression on crizotinib. ROS1 resistance mutations were identified in 53% of specimens, including nine (64%) of 14 non–brain metastasis specimens. ROS1 mutations included G2032R (41%), D2033N (6%), and S1986F (6%). Conclusion Compared with ALK rearrangements, ROS1 rearrangements are associated with lower rates of extrathoracic metastases, including fewer brain metastases, at initial metastatic diagnosis. ROS1 resistance mutations, particularly G2032R, appear to be the predominant mechanism of resistance to crizotinib, which underscores the need to develop novel ROS1 inhibitors with activity against these resistant mutants.
    Type of Medium: Online Resource
    ISSN: 2473-4284
    URL: Article
    DOI: 10.1200/PO.17.00063
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2017
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  • 4
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    SHP2 inhibition restores sensitivity in ALK-rearranged non-small-cell lung cancer resistant to ALK inhibitors
    Springer Science and Business Media LLC ; 2018
    In:  Nature Medicine Vol. 24, No. 4 ( 2018-4), p. 512-517
    Details
    In: Nature Medicine, Springer Science and Business Media LLC, Vol. 24, No. 4 ( 2018-4), p. 512-517
    Type of Medium: Online Resource
    ISSN: 1078-8956 , 1546-170X
    URL: Article
    DOI: 10.1038/nm.4497
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
    detail.hit.zdb_id: 1484517-9
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  • 5
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    Abstract 3144: Prediction of ALK mutations associated with acquired resistance to lorlatinib
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 3144-3144
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 3144-3144
    Abstract: Anaplastic lymphoma kinase (ALK) rearrangements are important therapeutic targets in non-small cell lung cancer. They are currently treated with the first-generation ALK inhibitor crizotnib followed by more potent, second-generation ALK inhibitors, such as ceritinib, alectinib, or brigatinib. We reported different spectrums of ALK resistance mutations in the biopsies from patients progressing on these drugs. G1202R mutation was found more frequently after treatment with second generation ALK inhibitors. In addition to these drugs, the third-generation ALK inhibitor lorlatinib is currently being evaluated in phase 2 clinical trial. Ba/F3 models indicated that all single ALK mutants are sensitive to lorlatinib and some compound ALK mutations are resistant to lorlatinib. In this study, we performed accelerated mutagenesis screen on Ba/F3 models to predict the resistance mutations which potentially emerge in the patients treated with lorlatinib. Briefly, Ba/F3 cells expressing wild type EML4-ALK or mutant EML4-ALK containing C1156Y, F1174C, L1196M, G1202R, or G1269A were exposed to N-ethyl-N-nitrosourea (ENU). After a 24-hour incubation in normal media, the cells were seeded in 96-well plates and incubated in lorlatinib for 4 weeks. ALK kinase domain was sequenced in clones growing in lorlatinib to identify possible new mutations. As a result, Ba/F3 cells harboring wild type EML4-ALK did not show any mutation on ALK kinase domain. Crizotinib was used as a control to validate the efficiency of mutagenesis. We identified eight different mutations in clones growing in crizotinib, and those were reflecting the spectrum of mutations in the crizotinib-treated patients. Ba/F3 cells with mutant EML4-ALK showed additional compound mutations after incubation with lorlatinib. Those mutations included L1196M + L1198F and G1202R + L1198F which showed high resistance to lorlatinib in Ba/F3 models. Ba/F3 cells with different mutant EML4-ALK showed a distinct spectrum and different frequency of additional mutations. In conclusion, this study predicted that no single mutation would emerge to confer resistance to lorlatinib. Thus, compound mutations and ALK-independent mechanisms become essential mechanisms for lorlatinib resistance. Citation Format: Satoshi Yoda, Leila Dardaei, Manrose Singh, Jeffrey A. Engelman, Alice T. Shaw, Aaron N. Hata. Prediction of ALK mutations associated with acquired resistance to lorlatinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3144. doi:10.1158/1538-7445.AM2017-3144
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-3144
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 6
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    Abstract A145: SHP2 inhibition restores sensitivity to ALK inhibitors in resistant ALK-rearranged NSCLC
    American Association for Cancer Research (AACR) ; 2018
    In:  Molecular Cancer Therapeutics Vol. 17, No. 1_Supplement ( 2018-01-01), p. A145-A145
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 17, No. 1_Supplement ( 2018-01-01), p. A145-A145
    Abstract: Most anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung tumors initially respond to small-molecule ALK inhibitors, but drug resistance often develops. After tumors develop resistance to highly potent 2nd-generation ALK inhibitors, approximately half harbor ALK resistance mutations, while the other half have other mechanisms of resistance. The latter often have activation of at least one of several different tyrosine kinases driving resistance. Such tumors are not expected to respond to the 3rd-generation ALK inhibitor, lorlatinib, which is able to overcome all clinically identified ALK resistance mutations, and further therapeutic options are limited. Herein, we deployed an shRNA screen of 1000 genes in multiple ALK inhibitor-resistant patient-derived cells (PDC) to discover sensitizers to ALK inhibition. This approach identified SHP2, a non-receptor protein tyrosine phosphatase, as a common targetable resistance node in multiple PDCs. SHP2 provides a parallel survival input downstream of multiple tyrosine kinases that promote resistance to ALK inhibitors. The recently discovered small-molecule SHP2 inhibitor, SHP099, in combination with the ALK TKI (tyrosine kinase inhibitor), ceritinib, halted the growth of resistant PDCs by preventing compensatory RAS and ERK1/2 reactivation. These findings suggest that combined ALK and SHP2 inhibition may be a promising therapeutic strategy for resistant cancers driven by several different ALK-independent resistance mechanisms. Citation Format: Leila Dardaei, Hui Qin Wang, Manrose Singh, Paul Fordjour, Satoshi Yoda, Grainne Kerr, Jinsheng Liang, Yichen Cao, Yan Chen, Justin Gainor, Luc Friboulet, Ibiayi Dagogo-Jack, David Myers, Emma Labrot, David Ruddy, Melissa Parks, Dana Lee, Richard DiCecca, Susan Moody, Huaixiang Hao, Morvarid Mohseni, Matthew LaMarche, Juliet Williams, Keith Hoffmaster, Giordano Caponigro, Alice Shaw, Aaron Hata, Cyril Benes, Fang Li, Jeffrey Engelman. SHP2 inhibition restores sensitivity to ALK inhibitors in resistant ALK-rearranged NSCLC [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 A145.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-17-A145
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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  • 7
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    Homeodomain transcription factor and tumor suppressor Prep1 is required to maintain genomic stability
    Proceedings of the National Academy of Sciences ; 2011
    In:  Proceedings of the National Academy of Sciences Vol. 108, No. 29 ( 2011-07-19)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 108, No. 29 ( 2011-07-19)
    Abstract: Our results support a model in which the tumor suppressor role of Prep1 is associated with the maintenance of genomic stability ( Fig. P1 ). Reduced expression of Prep1 (as in the majority of human cancers) is advantageous in the multistep process of tumorigenesis, because it accelerates the rate of accumulation of cancer-favoring mutations. It is noteworthy that, despite the occurrence of irreversible genetic events in Prep1 i/i MEFs, the cells still require reduction of Prep1 to manifest a fully transformed potential. Prep1 expression reverts some of the properties of these transformed cells, suggesting that a strategy based on the restoration of Prep1 function might have therapeutic effects in the fraction of human tumors ( 1 ) expressing very low levels of Prep1 . To determine the cellular processes that are implicated in the tumor suppressor function of Prep1 , we analyzed the behavior of cells in which Prep1 had been knocked down. We examined hypomorphic Prep1 i/i fetal liver cells and mouse embryonic fibroblasts (MEFs) using a biochemical technique for detecting DNA breaks (Comet assay) and immunological assays for markers of the DNA damage signaling cascade. We found that Prep1 -deficient cells exhibit increased basal DNA damage and a normal cellular response to DNA damage after γ-irradiation compared with WT cells. DNA content and cytogenetic analyses in MEFs also revealed a tendency for chromosomal aberrations, including alterations in chromosome copy number, in Prep1 i/i MEFs. To determine whether the observed DNA damage is an early or late consequence of the absence of Prep1 , we down-regulated Prep1 in normal human fibroblasts and used markers of DNA damage signaling to check for both DNA damage and the cellular response to damage. Down-regulation of Prep1 is rapidly followed by DNA damage. Furthermore, Prep1 knockdown is followed by an increase of chromosome-related modifications, such as a change in the compactness of heterochromatin, a higher-order chromosomal structure, which was indicated by a rapid increase in the trimethylation of a specific histone protein that helps compose chromatin. Additional molecular analysis confirmed the overall increase of this modification on Prep1 down-regulation in both mouse and human cells. However, chromatin modifications appear as a consequence rather than as a cause of DNA damage. Because genomic instability is associated with cell immortalization and cancer, we studied the immortalization kinetics of two WT and two Prep1 i/i littermate MEF cell lines in culture. Prep1 -deficient cells but not WT cells markedly increased their proliferative rates at later stages of cell culture. The causal link between genomic instability and cellular behavior is supported by a spontaneous genetic deletion in a genetic locus dubbed the Ink4a-Arf locus in one of the Prep1 i/i MEF lines analyzed. We also analyzed transformation, the cellular process that is known to trigger cancer, in MEFs by overexpressing the oncogene Ras and performing in vitro and in vivo transformation assays. Prep1 i/i MEFs were much more efficiently transformed by Ras compared with WT cells. Remarkably, expression of Prep1 partially rescued the transformation phenotype of Prep1 i/i MEFs. Finally, we studied whether a stable knockdown of Prep1 can affect oncogene-mediated senescence in human cells. In fact, in the absence of other lesions, introduction of an oncogene blocks cell proliferation-inducing senescence. This phenomenon is mediated by the increased expression of one specific tumor suppressor gene, p19-Arf. We showed that Prep1 down-regulation favors the bypass of oncogene-induced senescence and partially compromises Arf induction. Prep1 is essential during embryonic development. Mouse embryos lacking Prep1 die before gastrulation, a critical early step in embryonic development, because epiblast cells, which help determine the formation of the embryo, undergo apoptosis ( 2 ). Genetic data suggest that the Prep1 phenotype is related to DNA damage. However, embryos carrying a different Prep1 mutation—called a hypomorphic Prep1 mutation—that does not eliminate the gene but leads to very low (2%) levels of Prep1 mRNA—show incomplete development of organs, and in 75% of cases, they die at embryonic day 17.5 ( 3 ). The idea that Prep1 is a tumor suppressor stems from the observation that the fraction of homozygous mice bearing this Prep1 mutation and survive embryonic lethality often develops tumors. In addition, Prep1 insufficiency drastically accelerates the development of a type of lymphoma. Furthermore, a survey of more than 1,000 human cancers shows a dramatic reduction of Prep1 expression in a large proportion (70%) of the patients ( 1 ). The down-regulation of tumor suppressor genes, which help keep cancer in check, has been reported in a range of cancer types. Our recent studies revealed that the human homolog of one such mouse tumor suppressor protein (Prep1, which acts as a gene switch bearing a canonical structure called a homeodomain) is absent or down-regulated in 70% of human cancers ( 1 ). Extending those earlier findings, here, we report that Prep1 acts as a tumor suppressor most likely by helping cells maintain genomic stability. Although many tumor suppressor genes are known, the large proportion of human tumors in which the Prep1 gene is absent or down-regulated prompts a deep investigation of its function.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1105216108
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2011
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 8
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    Transcription factor PREP1 induces EMT and metastasis by controlling the TGF-β–SMAD3 pathway in non-small cell lung adenocarcinoma
    Proceedings of the National Academy of Sciences ; 2014
    In:  Proceedings of the National Academy of Sciences Vol. 111, No. 36 ( 2014-09-09)
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    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 111, No. 36 ( 2014-09-09)
    Abstract: Pre–B-cell leukemia homeobox (Pbx)-regulating protein-1 (Prep1) is a ubiquitous homeoprotein involved in early development, genomic stability, insulin sensitivity, and hematopoiesis. Previously we have shown that Prep1 is a haploinsufficient tumor suppressor that inhibits neoplastic transformation by competing with myeloid ecotropic integration site 1 for binding to the common heterodimeric partner Pbx1. Epithelial–mesenchymal transition (EMT) is controlled by complex networks of proinvasive transcription factors responsive to paracrine factors such as TGF-β. Here we show that, in addition to inhibiting primary tumor growth, PREP1 is a novel EMT inducer and prometastatic transcription factor. In human non-small cell lung cancer (NSCLC) cells, PREP1 overexpression is sufficient to trigger EMT, whereas PREP1 down-regulation inhibits the induction of EMT in response to TGF-β. PREP1 modulates the cellular sensitivity to TGF-β by inducing the small mothers against decapentaplegic homolog 3 (SMAD3) nuclear translocation through mechanisms dependent, at least in part, on PREP1-mediated transactivation of a regulatory element in the SMAD3 first intron. Along with the stabilization and accumulation of PBX1, PREP1 induces the expression of multiple activator protein 1 components including the proinvasive Fos-related antigen 1 (FRA-1) oncoprotein. Both FRA-1 and PBX1 are required for the mesenchymal changes triggered by PREP1 in lung tumor cells. Finally, we show that the PREP1-induced mesenchymal transformation correlates with significantly increased lung colonization by cells overexpressing PREP1. Accordingly, we have detected PREP1 accumulation in a large number of human brain metastases of various solid tumors, including NSCLC. These findings point to a novel role of the PREP1 homeoprotein in the control of the TGF-β pathway, EMT, and metastasis in NSCLC.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1407074111
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2014
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 9
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    Prep1 and Meis1 competition for Pbx1 binding regulates protein stability and tumorigenesis
    Proceedings of the National Academy of Sciences ; 2014
    In:  Proceedings of the National Academy of Sciences Vol. 111, No. 10 ( 2014-03-11)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 111, No. 10 ( 2014-03-11)
    Abstract: Pbx-regulating protein-1 ( Prep1 ) is a tumor suppressor, whereas myeloid ecotropic viral integration site-1 ( Meis1 ) is an oncogene. We show that, to perform these activities in mouse embryonic fibroblasts, both proteins competitively heterodimerize with pre–B-cell leukemia homeobox-1 (Pbx1). Meis1 alone transforms Prep1 -deficient fibroblasts, whereas Prep1 overexpression inhibits Meis1 tumorigenicity. Pbx1 can, therefore, alternatively act as an oncogene or tumor suppressor. Prep1 posttranslationally controls the level of Meis1, decreasing its stability by sequestering Pbx1. The different levels of Meis1 and the presence of Prep1 are followed at the transcriptional level by the induction of specific transcriptional signatures. The decrease of Meis1 prevents Meis1 interaction with Ddx3x and Ddx5, which are essential for Meis1 tumorigenesis, and modifies the growth-promoting DNA binding landscape of Meis1 to the growth-controlling landscape of Prep1. Hence, the key feature of Prep1 tumor-inhibiting activity is the control of Meis1 stability.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1321200111
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2014
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 10
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    Resensitization to Crizotinib by the Lorlatinib ALK Resistance Mutation L1198F
    Massachusetts Medical Society ; 2016
    In:  New England Journal of Medicine Vol. 374, No. 1 ( 2016-01-07), p. 54-61
    Details
    In: New England Journal of Medicine, Massachusetts Medical Society, Vol. 374, No. 1 ( 2016-01-07), p. 54-61
    Type of Medium: Online Resource
    ISSN: 0028-4793 , 1533-4406
    URL: Article
    DOI: 10.1056/NEJMoa1508887
    RVK:
    XA 10000
    Language: English
    Publisher: Massachusetts Medical Society
    Publication Date: 2016
    detail.hit.zdb_id: 1468837-2
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