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Article ; Online: The Role of Aneuploidy in Cancer Evolution.

Sansregret, Laurent / Swanton, Charles

Cold Spring Harbor perspectives in medicine

2017 Volume 7, Issue 1

Abstract: Chromosomal aberrations during cell division represent one of the first recognized features of human cancer cells, and modern detection methods have revealed the pervasiveness of aneuploidy in cancer. The ongoing karyotypic changes brought about by ... ...

Abstract	Chromosomal aberrations during cell division represent one of the first recognized features of human cancer cells, and modern detection methods have revealed the pervasiveness of aneuploidy in cancer. The ongoing karyotypic changes brought about by chromosomal instability (CIN) contribute to tumor heterogeneity, drug resistance, and treatment failure. Whole-chromosome and segmental aneuploidies resulting from CIN have been proposed to allow "macroevolutionary" leaps that may contribute to profound phenotypic change. In this review, we will outline evidence indicating that aneuploidy and CIN contribute to cancer evolution.
MeSH term(s)	Aneuploidy ; Animals ; Chromosomal Instability/genetics ; Drug Resistance/genetics ; Humans ; Mice ; Mitosis/genetics ; Neoplasms/genetics
Language	English
Publishing date	2017-01-03
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2157-1422
ISSN (online)	2157-1422
DOI	10.1101/cshperspect.a028373
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Article ; Online: Determinants and clinical implications of chromosomal instability in cancer.

Sansregret, Laurent / Vanhaesebroeck, Bart / Swanton, Charles

Nature reviews. Clinical oncology

2018 Volume 15, Issue 3, Page(s) 139–150

Abstract: Aberrant chromosomal architecture, ranging from small insertions or deletions to large chromosomal alterations, is one of the most common characteristics of cancer genomes. Chromosomal instability (CIN) underpins much of the intratumoural heterogeneity ... ...

Abstract	Aberrant chromosomal architecture, ranging from small insertions or deletions to large chromosomal alterations, is one of the most common characteristics of cancer genomes. Chromosomal instability (CIN) underpins much of the intratumoural heterogeneity observed in cancers and drives phenotypic adaptation during tumour evolution. Thus, an urgent need exists to increase our efforts to target CIN as if it were a molecular entity. Indeed, CIN accelerates the development of anticancer drug resistance, often leading to treatment failure and disease recurrence, which limit the effectiveness of most current therapies. Identifying novel strategies to modulate CIN and to exploit the fitness cost associated with aneuploidy in cancer is, therefore, of paramount importance for the successful treatment of cancer. Modern sequencing and analytical methods greatly facilitate the identification and cataloguing of somatic copy-number alterations and offer new possibilities to better exploit the dynamic process of CIN. In this Review, we describe the principles governing CIN propagation in cancer and how CIN might influence sensitivity to immune-checkpoint inhibition, and survey the vulnerabilities associated with CIN that offer potential therapeutic opportunities.
MeSH term(s)	Aneuploidy ; Chromosomal Instability/genetics ; DNA Copy Number Variations/genetics ; Genetic Heterogeneity ; Genome, Human/genetics ; Humans ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/pathology
Language	English
Publishing date	2018-01-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2491410-1
ISSN	1759-4782 ; 1759-4774
ISSN (online)	1759-4782
ISSN	1759-4774
DOI	10.1038/nrclinonc.2017.198
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Article ; Online: Born equal: dual safeguards for daughter cell size symmetry.

Sansregret, Laurent / Petronczki, Mark

Cell

2013 Volume 154, Issue 2, Page(s) 269–271

Abstract: Development and homeostasis require repeated symmetric cell divisions, which in turn depend on a centered mitotic spindle. In this issue, Kiyomitsu and Cheeseman uncover two mechanisms that ensure correct spindle positioning in anaphase: cortical dynein ... ...

Abstract	Development and homeostasis require repeated symmetric cell divisions, which in turn depend on a centered mitotic spindle. In this issue, Kiyomitsu and Cheeseman uncover two mechanisms that ensure correct spindle positioning in anaphase: cortical dynein for pulling the spindle to the cell center and asymmetric membrane elongation that adjusts the position of the cell center to the cleavage plane.
MeSH term(s)	Anaphase ; Animals ; Cell Membrane/metabolism ; Dyneins/metabolism ; Humans ; Spindle Apparatus/metabolism
Chemical Substances	Dyneins (EC 3.6.4.2)
Language	English
Publishing date	2013-07-18
Publishing country	United States
Document type	Comment ; Journal Article
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2013.06.035
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Article ; Online: Gene signatures of genomic instability as prognostic tools for breast cancer.

Sansregret, Laurent / Nepveu, Alain

Future oncology (London, England)

2011 Volume 7, Issue 5, Page(s) 591–594

MeSH term(s)	Breast Neoplasms/diagnosis ; Breast Neoplasms/genetics ; Disease-Free Survival ; Female ; Gene Expression Profiling ; Genomic Instability ; Homeodomain Proteins/genetics ; Humans ; Nuclear Proteins/genetics ; Prognosis ; Repressor Proteins/genetics
Chemical Substances	CUX1 protein, human ; Homeodomain Proteins ; Nuclear Proteins ; Repressor Proteins
Language	English
Publishing date	2011-05
Publishing country	England
Document type	Editorial
ZDB-ID	2184533-5
ISSN	1744-8301 ; 1479-6694
ISSN (online)	1744-8301
ISSN	1479-6694
DOI	10.2217/fon.11.34
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Article ; Online: Direct and selective pharmacological disruption of the YAP-TEAD interface by IAG933 inhibits Hippo-dependent and RAS-MAPK-altered cancers.

Chapeau, Emilie A / Sansregret, Laurent / Galli, Giorgio G / Chène, Patrick / Wartmann, Markus / Mourikis, Thanos P / Jaaks, Patricia / Baltschukat, Sabrina / Barbosa, Ines A M / Bauer, Daniel / Brachmann, Saskia M / Delaunay, Clara / Estadieu, Claire / Faris, Jason E / Furet, Pascal / Harlfinger, Stefanie / Hueber, Andreas / Jiménez Núñez, Eloísa / Kodack, David P /

Mandon, Emeline / Martin, Typhaine / Mesrouze, Yannick / Romanet, Vincent / Scheufler, Clemens / Sellner, Holger / Stamm, Christelle / Sterker, Dario / Tordella, Luca / Hofmann, Francesco / Soldermann, Nicolas / Schmelzle, Tobias

Nature cancer

2024

Abstract: The YAP-TEAD protein-protein interaction mediates YAP oncogenic functions downstream of the Hippo pathway. To date, available YAP-TEAD pharmacologic agents bind into the lipid pocket of TEAD, targeting the interaction indirectly via allosteric changes. ... ...

Abstract	The YAP-TEAD protein-protein interaction mediates YAP oncogenic functions downstream of the Hippo pathway. To date, available YAP-TEAD pharmacologic agents bind into the lipid pocket of TEAD, targeting the interaction indirectly via allosteric changes. However, the consequences of a direct pharmacological disruption of the interface between YAP and TEADs remain largely unexplored. Here, we present IAG933 and its analogs as potent first-in-class and selective disruptors of the YAP-TEAD protein-protein interaction with suitable properties to enter clinical trials. Pharmacologic abrogation of the interaction with all four TEAD paralogs resulted in YAP eviction from chromatin and reduced Hippo-mediated transcription and induction of cell death. In vivo, deep tumor regression was observed in Hippo-driven mesothelioma xenografts at tolerated doses in animal models as well as in Hippo-altered cancer models outside mesothelioma. Importantly this also extended to larger tumor indications, such as lung, pancreatic and colorectal cancer, in combination with RTK, KRAS-mutant selective and MAPK inhibitors, leading to more efficacious and durable responses. Clinical evaluation of IAG933 is underway.
Language	English
Publishing date	2024-04-02
Publishing country	England
Document type	Journal Article
ISSN	2662-1347
ISSN (online)	2662-1347
DOI	10.1038/s43018-024-00754-9
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Article ; Online: CRISPR Screening Identifies Mechanisms of Resistance to KRASG12C and SHP2 Inhibitor Combinations in Non-Small Cell Lung Cancer.

Cancer research

2023 Volume 83, Issue 24, Page(s) 4130–4141

Abstract: Although KRASG12C inhibitors show clinical activity in patients with KRAS G12C mutated non-small cell lung cancer (NSCLC) and other solid tumor malignancies, response is limited by multiple mechanisms of resistance. The KRASG12C inhibitor JDQ443 shows ... ...

Abstract	Although KRASG12C inhibitors show clinical activity in patients with KRAS G12C mutated non-small cell lung cancer (NSCLC) and other solid tumor malignancies, response is limited by multiple mechanisms of resistance. The KRASG12C inhibitor JDQ443 shows enhanced preclinical antitumor activity combined with the SHP2 inhibitor TNO155, and the combination is currently under clinical evaluation. To identify rational combination strategies that could help overcome or prevent some types of resistance, we evaluated the duration of tumor responses to JDQ443 ± TNO155, alone or combined with the PI3Kα inhibitor alpelisib and/or the cyclin-dependent kinase 4/6 inhibitor ribociclib, in xenograft models derived from a KRASG12C-mutant NSCLC line and investigated the genetic mechanisms associated with loss of response to combined KRASG12C/SHP2 inhibition. Tumor regression by single-agent JDQ443 at clinically relevant doses lasted on average 2 weeks and was increasingly extended by the double, triple, or quadruple combinations. Growth resumption was accompanied by progressively increased KRAS G12C amplification. Functional genome-wide CRISPR screening in KRASG12C-dependent NSCLC lines with distinct mutational profiles to identify adaptive mechanisms of resistance revealed sensitizing and rescuing genetic interactions with KRASG12C/SHP2 coinhibition; FGFR1 loss was the strongest sensitizer, and PTEN loss the strongest rescuer. Consistently, the antiproliferative activity of KRASG12C/SHP2 inhibition was strongly enhanced by PI3K inhibitors. Overall, KRAS G12C amplification and alterations of the MAPK/PI3K pathway were predominant mechanisms of resistance to combined KRASG12C/SHP2 inhibitors in preclinical settings. The biological nodes identified by CRISPR screening might provide additional starting points for effective combination treatments. Significance: Identification of resistance mechanisms to KRASG12C/SHP2 coinhibition highlights the need for additional combination therapies for lung cancer beyond on-pathway combinations and offers the basis for development of more effective combination approaches. See related commentary by Johnson and Haigis, p. 4005.
MeSH term(s)	Humans ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/pathology ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics ; Lung Neoplasms/pathology ; Phosphatidylinositol 3-Kinases/genetics ; Clustered Regularly Interspaced Short Palindromic Repeats ; Proto-Oncogene Proteins p21(ras)/genetics ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Early Detection of Cancer ; Enzyme Inhibitors/therapeutic use ; Mutation ; Cell Line, Tumor
Chemical Substances	Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; JDQ443 ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; Protein Kinase Inhibitors ; Enzyme Inhibitors
Language	English
Publishing date	2023-11-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-23-1127
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Article: The multiple roles of CUX1: insights from mouse models and cell-based assays.

Sansregret, Laurent / Nepveu, Alain

Gene

2008 Volume 412, Issue 1-2, Page(s) 84–94

Abstract: Cux (Cut homeobox) genes are present in all metazoans. Early reports described many phenotypes caused by cut mutations in Drosophila melanogaster. In vertebrates, CUX1 was originally characterized as the CCAAT-displacement protein (CDP). Another line of ... ...

Abstract	Cux (Cut homeobox) genes are present in all metazoans. Early reports described many phenotypes caused by cut mutations in Drosophila melanogaster. In vertebrates, CUX1 was originally characterized as the CCAAT-displacement protein (CDP). Another line of investigation revealed the presence of CUX1 within a multi-protein complex called the histone nuclear factor D (HiNF-D). Recent studies led to the identification of several CUX1 isoforms with distinct DNA binding and transcriptional properties. While the CCAAT-displacement activity was implicated in the transcriptional repression of several genes, some CUX1 isoforms were found to participate in the transcriptional activation of some genes. The expression and activity of CUX1 was shown to be regulated through the cell cycle and to be a target of TGF-beta signaling. Mechanisms of regulation include alternative transcription initiation, proteolytic processing, phosphorylation and acetylation. Cell-based assays have established a role for CUX1 in the control of cell cycle progression, cell motility and invasion. In the mouse, gene inactivation as well as over-expression in transgenic mice has revealed phenotypes in multiple organs and cell types. While some phenotypes could be explained by the presumed functions of CUX1 in the affected cells, other phenotypes invoked non-cell-autonomous effects that suggest regulatory functions with an impact on cell-cell interactions. The implication of CUX1 in cancer was suggested first from its over-expression in primary tumors and cancer cell lines and was later confirmed in mouse models.
MeSH term(s)	Animals ; Cell Differentiation/genetics ; Cell Differentiation/physiology ; Cell Line ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/physiology ; Genes, Homeobox ; Homeodomain Proteins/genetics ; Homeodomain Proteins/physiology ; Humans ; Mice ; Mice, Knockout ; Mice, Transgenic ; Models, Animal ; Mutation ; Neoplasms/etiology ; Neoplasms/genetics ; Nuclear Proteins/genetics ; Nuclear Proteins/physiology ; Protein Processing, Post-Translational ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Repressor Proteins/genetics ; Repressor Proteins/physiology ; Transforming Growth Factor beta/metabolism
Chemical Substances	Cux1 protein, mouse ; DNA-Binding Proteins ; HINF-D protein, human ; Homeodomain Proteins ; Nuclear Proteins ; RNA, Messenger ; Repressor Proteins ; Transforming Growth Factor beta
Language	English
Publishing date	2008-02-02
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	391792-7
ISSN	1879-0038 ; 0378-1119
ISSN (online)	1879-0038
ISSN	0378-1119
DOI	10.1016/j.gene.2008.01.017
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Article: Hyperphosphorylation by Cyclin B/CDK1 in Mitosis Resets CUX1 DNA Binding Clock at Each Cell Cycle

Sansregret, Laurent / Gallo, David / Santaguida, Marianne / Leduy, Lam / Harada, Ryoko / Nepveu, Alain

Journal of biological chemistry. 2010 Oct. 22, v. 285, no. 43

2010

Abstract: The p110 CUX1 homeodomain protein participates in the activation of DNA replication genes in part by increasing the affinity of E2F factors for the promoters of these genes. CUX1 expression is very weak in quiescent cells and increases during G₁. ... ...

Abstract	The p110 CUX1 homeodomain protein participates in the activation of DNA replication genes in part by increasing the affinity of E2F factors for the promoters of these genes. CUX1 expression is very weak in quiescent cells and increases during G₁. Biochemical activities associated with transcriptional activation by CUX1 are potentiated by post-translational modifications in late G₁, notably a proteolytic processing event that generates p110 CUX1. Constitutive expression of p110 CUX1, as observed in some transformed cells, leads to accelerated entry into the S phase. In this study, we investigated the post-translation regulation of CUX1 during mitosis and the early G₁ phases of proliferating cells. We observed a major electrophoretic mobility shift and a complete inhibition of DNA binding during mitosis. We show that cyclin B/CDK1 interacts with CUX1 and phosphorylates it at multiple sites. Serine to alanine replacement mutations at 10 SP dipeptide sites were required to restore DNA binding in mitosis. Passage into G₁ was associated with the degradation of some p110 CUX1 proteins, and the remaining proteins were gradually dephosphorylated. Indirect immunofluorescence and subfractionation assays using a phospho-specific antibody showed that most of the phosphorylated protein remained in the cytoplasm, whereas the dephosphorylated protein was preferentially located in the nucleus. Globally, our results indicate that the hyperphosphorylation of CUX1 by cyclin B/CDK1 inhibits its DNA binding activity in mitosis and interferes with its nuclear localization following cell division and formation of the nuclear membrane, whereas dephosphorylation and de novo synthesis contribute to gradually restore CUX1 expression and activity in G₁.
Language	English
Dates of publication	2010-1022
Size	p. 32834-32843.
Publishing place	American Society for Biochemistry and Molecular Biology
Document type	Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
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Article ; Online: Cdk1 inactivation terminates mitotic checkpoint surveillance and stabilizes kinetochore attachments in anaphase.

Vázquez-Novelle, María Dolores / Sansregret, Laurent / Dick, Amalie E / Smith, Christopher A / McAinsh, Andrew D / Gerlich, Daniel W / Petronczki, Mark

Current biology : CB

2014 Volume 24, Issue 6, Page(s) 638–645

Abstract: Two mechanisms safeguard the bipolar attachment of chromosomes in mitosis. A correction mechanism destabilizes erroneous attachments that do not generate tension across sister kinetochores [1]. In response to unattached kinetochores, the mitotic ... ...

Abstract	Two mechanisms safeguard the bipolar attachment of chromosomes in mitosis. A correction mechanism destabilizes erroneous attachments that do not generate tension across sister kinetochores [1]. In response to unattached kinetochores, the mitotic checkpoint delays anaphase onset by inhibiting the anaphase-promoting complex/cyclosome (APC/C(Cdc20)) [2]. Upon satisfaction of both pathways, the APC/C(Cdc20) elicits the degradation of securin and cyclin B [3]. This liberates separase triggering sister chromatid disjunction and inactivates cyclin-dependent kinase 1 (Cdk1) causing mitotic exit. How eukaryotic cells avoid the engagement of attachment monitoring mechanisms when sister chromatids split and tension is lost at anaphase is poorly understood [4]. Here we show that Cdk1 inactivation disables mitotic checkpoint surveillance at anaphase onset in human cells. Preventing cyclin B1 proteolysis at the time of sister chromatid disjunction destabilizes kinetochore-microtubule attachments and triggers the engagement of the mitotic checkpoint. As a consequence, mitotic checkpoint proteins accumulate at anaphase kinetochores, the APC/C(Cdc20) is inhibited, and securin reaccumulates. Conversely, acute pharmacological inhibition of Cdk1 abrogates the engagement and maintenance of the mitotic checkpoint upon microtubule depolymerization. We propose that the simultaneous destruction of securin and cyclin B elicited by the APC/C(Cdc20) couples chromosome segregation to the dissolution of attachment monitoring mechanisms during mitotic exit.
MeSH term(s)	Anaphase/physiology ; CDC2 Protein Kinase/physiology ; Chromatids/physiology ; Cyclin B/physiology ; Cyclin B1/physiology ; HeLa Cells ; Humans ; Kinetochores/physiology ; M Phase Cell Cycle Checkpoints/physiology ; Nondisjunction, Genetic/physiology ; Separase/physiology
Chemical Substances	Cyclin B ; Cyclin B1 ; CDC2 Protein Kinase (EC 2.7.11.22) ; Separase (EC 3.4.22.49)
Language	English
Publishing date	2014-02-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1071731-6
ISSN	1879-0445 ; 0960-9822
ISSN (online)	1879-0445
ISSN	0960-9822
DOI	10.1016/j.cub.2014.01.034
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Article ; Online: Hyperphosphorylation by cyclin B/CDK1 in mitosis resets CUX1 DNA binding clock at each cell cycle.

Sansregret, Laurent / Gallo, David / Santaguida, Marianne / Leduy, Lam / Harada, Ryoko / Nepveu, Alain

The Journal of biological chemistry

2010 Volume 285, Issue 43, Page(s) 32834–32843

Abstract	The p110 CUX1 homeodomain protein participates in the activation of DNA replication genes in part by increasing the affinity of E2F factors for the promoters of these genes. CUX1 expression is very weak in quiescent cells and increases during G(1). Biochemical activities associated with transcriptional activation by CUX1 are potentiated by post-translational modifications in late G(1), notably a proteolytic processing event that generates p110 CUX1. Constitutive expression of p110 CUX1, as observed in some transformed cells, leads to accelerated entry into the S phase. In this study, we investigated the post-translation regulation of CUX1 during mitosis and the early G(1) phases of proliferating cells. We observed a major electrophoretic mobility shift and a complete inhibition of DNA binding during mitosis. We show that cyclin B/CDK1 interacts with CUX1 and phosphorylates it at multiple sites. Serine to alanine replacement mutations at 10 SP dipeptide sites were required to restore DNA binding in mitosis. Passage into G(1) was associated with the degradation of some p110 CUX1 proteins, and the remaining proteins were gradually dephosphorylated. Indirect immunofluorescence and subfractionation assays using a phospho-specific antibody showed that most of the phosphorylated protein remained in the cytoplasm, whereas the dephosphorylated protein was preferentially located in the nucleus. Globally, our results indicate that the hyperphosphorylation of CUX1 by cyclin B/CDK1 inhibits its DNA binding activity in mitosis and interferes with its nuclear localization following cell division and formation of the nuclear membrane, whereas dephosphorylation and de novo synthesis contribute to gradually restore CUX1 expression and activity in G(1).
MeSH term(s)	Active Transport, Cell Nucleus/physiology ; Animals ; CDC2 Protein Kinase/genetics ; CDC2 Protein Kinase/metabolism ; Cell Line ; Cell Nucleus/genetics ; Cell Nucleus/metabolism ; Cyclin B/genetics ; Cyclin B/metabolism ; DNA/genetics ; DNA/metabolism ; G1 Phase/physiology ; Homeodomain Proteins/genetics ; Homeodomain Proteins/metabolism ; Humans ; Mice ; Mitosis/physiology ; Mutation, Missense ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Phosphorylation/physiology ; Protein Binding/physiology ; Repressor Proteins/genetics ; Repressor Proteins/metabolism
Chemical Substances	Cux1 protein, mouse ; Cyclin B ; Homeodomain Proteins ; Nuclear Proteins ; Repressor Proteins ; DNA (9007-49-2) ; CDC2 Protein Kinase (EC 2.7.11.22)
Language	English
Publishing date	2010-08-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M110.156406
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