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1.
Commun Biol ; 5(1): 106, 2022 02 03.
Article de Anglais | MEDLINE | ID: mdl-35115660

RÉSUMÉ

Oncolytic viruses are being tested in clinical trials, including in women with ovarian cancer. We use a drug-repurposing approach to identify existing drugs that enhance the activity of oncolytic adenoviruses. This reveals that carvedilol, a ß-arrestin-biased ß-blocker, synergises with both wild-type adenovirus and the E1A-CR2-deleted oncolytic adenovirus, dl922-947. Synergy is not due to ß-adrenergic blockade but is dependent on ß-arrestins and is reversed by ß-arrestin CRISPR gene editing. Co-treatment with dl922-947 and carvedilol causes increased viral DNA replication, greater viral protein expression and higher titres of infectious viral particles. Carvedilol also enhances viral efficacy in orthotopic, intraperitoneal murine models, achieving more rapid tumour clearance than virus alone. Increased anti-cancer activity is associated with an intratumoural inflammatory cell infiltrate and systemic cytokine release. In summary, carvedilol augments the activity of oncolytic adenoviruses via ß-arrestins to re-wire cytokine networks and innate immunity and could therefore improve oncolytic viruses for cancer patient treatment.


Sujet(s)
Adenoviridae , Carvédilol/pharmacologie , Immunité innée , Thérapie virale de cancers , Virus oncolytiques , Tumeurs de l'ovaire/thérapie , Antagonistes des récepteurs alpha-1 adrénergiques/pharmacologie , Antagonistes des récepteurs alpha-1 adrénergiques/usage thérapeutique , Animaux , Carvédilol/usage thérapeutique , Lignée cellulaire tumorale , Femelle , Humains , Souris , Tumeurs expérimentales/traitement médicamenteux , Tumeurs de l'ovaire/immunologie , Tests d'activité antitumorale sur modèle de xénogreffe , bêta-Arrestines/métabolisme
2.
Cell Death Dis ; 12(4): 395, 2021 04 14.
Article de Anglais | MEDLINE | ID: mdl-33854036

RÉSUMÉ

High-grade serous cancer (HGSC) accounts for ~67% of all ovarian cancer deaths. Although initially sensitive to platinum chemotherapy, resistance is inevitable and there is an unmet clinical need for novel therapies that can circumvent this event. We performed a drug screen with 1177 FDA-approved drugs and identified the hydroxyquinoline drug, chloroxine. In extensive validation experiments, chloroxine restored sensitivity to both cisplatin and carboplatin, demonstrating broad synergy in our range of experimental models of platinum-resistant HGSC. Synergy was independent of chloroxine's predicted ionophore activity and did not relate to platinum uptake as measured by atomic absorption spectroscopy. Further mechanistic investigation revealed that chloroxine overrides DNA damage tolerance in platinum-resistant HGSC. Co-treatment with carboplatin and chloroxine (but not either drug alone) caused an increase in γH2AX expression, followed by a reduction in platinum-induced RAD51 foci. Moreover, this unrepaired DNA damage was associated with p53 stabilisation, cell cycle re-entry and triggering of caspase 3/7-mediated cell death. Finally, in our platinum-resistant, intraperitoneal in vivo model, treatment with carboplatin alone resulted in a transient tumour response followed by tumour regrowth. In contrast, treatment with chloroxine and carboplatin combined, was able to maintain tumour volume at baseline for over 4 months. In conclusion, our novel results show that chloroxine facilitates platinum-induced DNA damage to restore platinum sensitivity in HGSC. Since chloroxine is already licensed, this exciting combination therapy could now be rapidly translated for patient benefit.


Sujet(s)
Chloroquinoléinols/pharmacologie , Altération de l'ADN/effets des médicaments et des substances chimiques , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Tumeurs de l'ovaire/traitement médicamenteux , Platine/pharmacologie , Animaux , Antinéoplasiques/pharmacologie , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Carboplatine/pharmacologie , Cisplatine/pharmacologie , Cystadénocarcinome séreux/traitement médicamenteux , Cystadénocarcinome séreux/anatomopathologie , Résistance aux médicaments antinéoplasiques/génétique , Femelle , Humains , Souris transgéniques , Tumeurs de l'ovaire/génétique
3.
Nat Commun ; 10(1): 2030, 2019 05 02.
Article de Anglais | MEDLINE | ID: mdl-31048689

RÉSUMÉ

Acquired resistance to MEK1/2 inhibitors (MEKi) arises through amplification of BRAFV600E or KRASG13D to reinstate ERK1/2 signalling. Here we show that BRAFV600E amplification and MEKi resistance are reversible following drug withdrawal. Cells with BRAFV600E amplification are addicted to MEKi to maintain a precise level of ERK1/2 signalling that is optimal for cell proliferation and survival, and tumour growth in vivo. Robust ERK1/2 activation following MEKi withdrawal drives a p57KIP2-dependent G1 cell cycle arrest and senescence or expression of NOXA and cell death, selecting against those cells with amplified BRAFV600E. p57KIP2 expression is required for loss of BRAFV600E amplification and reversal of MEKi resistance. Thus, BRAFV600E amplification confers a selective disadvantage during drug withdrawal, validating intermittent dosing to forestall resistance. In contrast, resistance driven by KRASG13D amplification is not reversible; rather ERK1/2 hyperactivation drives ZEB1-dependent epithelial-to-mesenchymal transition and chemoresistance, arguing strongly against the use of drug holidays in cases of KRASG13D amplification.


Sujet(s)
Antinéoplasiques/pharmacologie , Résistance aux médicaments antinéoplasiques/génétique , Tumeurs/traitement médicamenteux , Inhibiteurs de protéines kinases/pharmacologie , Protéines proto-oncogènes B-raf/génétique , Protéines proto-oncogènes p21(ras)/génétique , Antinéoplasiques/usage thérapeutique , Apoptose/effets des médicaments et des substances chimiques , Apoptose/génétique , Benzimidazoles/pharmacologie , Benzimidazoles/usage thérapeutique , Lignée cellulaire tumorale , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Transition épithélio-mésenchymateuse/effets des médicaments et des substances chimiques , Transition épithélio-mésenchymateuse/génétique , Femelle , Amplification de gène/effets des médicaments et des substances chimiques , Régulation de l'expression des gènes tumoraux/effets des médicaments et des substances chimiques , Humains , MAP Kinase Kinase 1/antagonistes et inhibiteurs , MAP Kinase Kinase 2/antagonistes et inhibiteurs , Système de signalisation des MAP kinases/effets des médicaments et des substances chimiques , Système de signalisation des MAP kinases/génétique , Mâle , Mitogen-Activated Protein Kinase 1/métabolisme , Mitogen-Activated Protein Kinase 3/métabolisme , Tumeurs/génétique , Inhibiteurs de protéines kinases/usage thérapeutique , Abstention thérapeutique , Facteur de transcription Zeb1/métabolisme
4.
Proc Natl Acad Sci U S A ; 112(4): 1059-64, 2015 Jan 27.
Article de Anglais | MEDLINE | ID: mdl-25583481

RÉSUMÉ

Alterations of mitochondrial metabolism and genomic instability have been implicated in tumorigenesis in multiple tissues. High-grade glioma (HGG), one of the most lethal human neoplasms, displays genetic modifications of Krebs cycle components as well as electron transport chain (ETC) alterations. Furthermore, the p53 tumor suppressor, which has emerged as a key regulator of mitochondrial respiration at the expense of glycolysis, is genetically inactivated in a large proportion of HGG cases. Therefore, it is becoming evident that genetic modifications can affect cell metabolism in HGG; however, it is currently unclear whether mitochondrial metabolism alterations could vice versa promote genomic instability as a mechanism for neoplastic transformation. Here, we show that, in neural progenitor/stem cells (NPCs), which can act as HGG cell of origin, inhibition of mitochondrial metabolism leads to p53 genetic inactivation. Impairment of respiration via inhibition of complex I or decreased mitochondrial DNA copy number leads to p53 genetic loss and a glycolytic switch. p53 genetic inactivation in ETC-impaired neural stem cells is caused by increased reactive oxygen species and associated oxidative DNA damage. ETC-impaired cells display a marked growth advantage in the presence or absence of oncogenic RAS, and form undifferentiated tumors when transplanted into the mouse brain. Finally, p53 mutations correlated with alterations in ETC subunit composition and activity in primary glioma-initiating neural stem cells. Together, these findings provide previously unidentified insights into the relationship between mitochondria, genomic stability, and tumor suppressive control, with implications for our understanding of brain cancer pathogenesis.


Sujet(s)
Tumeurs du cerveau , Transformation cellulaire néoplasique , Gliome , Cellules souches neurales/métabolisme , Protéine p53 suppresseur de tumeur , Animaux , Tumeurs du cerveau/génétique , Tumeurs du cerveau/métabolisme , Tumeurs du cerveau/anatomopathologie , Transformation cellulaire néoplasique/génétique , Transformation cellulaire néoplasique/métabolisme , Transformation cellulaire néoplasique/anatomopathologie , Cycle citrique/génétique , Altération de l'ADN , Complexe enzymatique de la chaine respiratoire mitochondriale/génétique , Complexe enzymatique de la chaine respiratoire mitochondriale/métabolisme , Gliome/génétique , Gliome/métabolisme , Gliome/anatomopathologie , Glycolyse/génétique , Humains , Souris , Souris de lignée NOD , Souris SCID , Mutation , Cellules souches neurales/anatomopathologie , Oxydoréduction , Protéine p53 suppresseur de tumeur/génétique , Protéine p53 suppresseur de tumeur/métabolisme
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