Les cancers du sein hormono-indépendants et HER2 non amplifiés, dites triples négatives (TN), représentent 30 % des tumeurs du sein. Elles sont de mauvais pronostic et ne bénéficient pas actuellement de thérapeutiques ciblées.Les tumeurs du sein apocrine moléculaire (AM) sont des tumeurs qui se caractérisent par l’absence de récepteurs hormonaux et la présence du récepteur aux androgènes (RA) dont la voie de signalisation est activée. Dans 50 % des cas elles sont HER2 négatives, et entrent alors dans la catégorie des TN.Le rôle de cette signalisation androgénique est mal connu. Cependant elle apparait comme une cible thérapeutique intéressante dans ce groupe de tumeur ne bénéficiant pas des thérapies ciblées. De plus peu de modèles précliniques représentatifs des tumeurs AM ont été publiés.Dans ce projet nous avons exploré le RA et sa signalisation à partir de modèles de lignées cellulaires.Nous avons d’abord caractérisé ces modèles sur le plan mutationnel en séquençant le RA et en recherchant des altérations moléculaires dans les voies de signalisation des récepteurs hormonaux et des facteurs de croissance puis sur le plan transcritpomique en vérifiant la présence d’une signature AM moléculaire et en recherchant des variants d’épissage du RA.Nous avons ensuite pu mettre en évidence une régulation de la prolifération et de la clonogénicité de ces lignées après blocage du RA et de sa voie de signalisation par invalidation de son expression par siRNA.Nous avons finalement pu vérifier dans plusieurs de ces modèles qu’un traitement par différents agonistes et antagonistes ciblant le RA permettait de moduler la prolifération et l’expression des gènes cibles du RA. / Hormone-independent and non-amplified HER2 breast cancers, or triple negative (TN), represent 30% of breast tumors. They have a poor prognosis and do not currently benefit from targeted therapies.Molecular apocrine (MA) breast cancers are characterized by the absence of hormone receptors and the presence of the androgen receptor (AR) which signaling pathway is activated. In 50% of cases they are HER2 negative, and then fall into the category of TN.The role of the androgen signaling is poorly understood. However the AR appears as an attractive therapeutic target in this group of tumors without targeted therapies. Moreover few preclinical models of MA have been published.In this project we explored the AR and its signaling in cell lines models.We first characterized these models on the mutational level by sequencing the AR and seeking molecular alterations in the signaling pathways of hormone receptors and growth factors. Then on the transcritpomique level by checking the presence of a molecular MA signature and seeking the AR splice variants.We then could highlight a regulation of cell proliferation and clonogenicity in these cell lines by blocking the AR and its signaling pathway with siRNAs.We were finally able to check in several of these models that treatment with different agonists and antagonists targeting the AR allowed to modulate cell proliferation and the expression of AR target genes.

Introdução: O câncer de próstata metastático resistente à castração apresenta sobrevida inferior a 30% em cinco anos, e o único tratamento disponível para os pacientes até pouco tempo atrás era o docetaxel. Com o maior entendimento dos mecanismos de resistência desse câncer às terapias utilizadas, novas drogas foram desenvolvidas, entre elas a abiraterona, que atua no bloqueio da enzima 17-? desidrogenase-hidroxiesteroide e a enzalutamida que age diretamente nos receptores de androgênios. Foi realizada uma revisão sistemática dos estudos que avaliaram a eficácia e segurança da abiraterona mais prednisona e da enzalutamida em pacientes com CPMRC, tanto previamente quanto posteriormente ao tratamento com docetaxel. Métodos: A pesquisa bibliográfica foi realizada em março de 2016 nas bases da Pubmed, Google Acadêmico e ClinicalTrials.gov. Os seguintes termos de pesquisa foram utilizados \"prostate cancer metastatic resistent\", \"prostate cancer\", \"abiraterone\" e enzalutamide\", restringido a estudos clínicos randomizados fase III, duplo cego e multicêntrico, publicados nos idiomas inglês, espanhol. Os estudos selecionados foram analisados de forma independente por LRM e AAN. Os critérios para análise foram a sobrevida global (SG), sobrevida livre de progressão (SLP) e o tempo até a progressão do PSA (TP PSA), previamente e após o uso de docetaxel. Resultados: Foram identificados 53 estudos. Aplicando os critérios de inclusão foram selecionados quatro estudos que juntos somaram uma população de 5.199 (2.394 pacientes após docetaxel e 2.805 pacientes previamente ao uso do docetaxel). Em relação a SG, a abiraterona reduziu o risco de morte em 26% após docetaxel (HR 0,74 95% IC 0,64-0,86) e 19% no pré-docetaxel (HR 0,81 95% IC 0,70-0,93), e a enzalutamida reduziu em 37% após (HR 0,63 95% IC, 0,53-0,75) e 23% no pré-docetaxel (HR 0,77 95% IC 0,67-0,88). Em relação a SLPr, abiraterona retardou a progressão da doença em 34% após (HR 0,66 95% IC 0,58-0,76) e 48% na pré-quimio (HR 0,52 95% IC 0,45-0,61), e a enzalutamida em 60% após quimio (HR 0,40 95% IC 0,35-0,47) e 68% na pré-quimio (HR 0,32 95% IC 0,28-0,36). Abiraterona aumentou o tempo até a progressão do PSA em 64% após quimio (HR 0,36 95% IC 0,52-0,78) e 50% na pré-quimio (HR 0,50 95% IC 0,43- 0,58), e a enzalutamida em 75% após quimio (HR 0,25 95% IC 0,20-0,30) e 83% na pré- quimio (HR 0,17 95% IC 0,15-0,20). Conclusão: Tanto abiraterona quanto enzalutamida demonstraram melhores resultados no aumento da SG, da SLPr e do TP PSA no tratamento de pacientes com CPMRC. Não há um estudo comparativo direto e devido a diferenças nos critérios de inclusão e dos grupos comparadores entre esses estudos clínicos, não é possível uma análise indireta entre tais medicamentos. Assim, questões como qual a melhor estratégia de tratamento na pré e pós-quimio e o sequenciamento ideal para enfrentamento do CPMRC não podem ser respondidas. / Introduction: Castrate-resistant metastatic prostate cancer presents survival less than 30% in five years, and the only treatment available to patients until recently was docetaxel. With the greater understanding of the mechanisms of resistance of this cancer to the therapies used, new drugs have been developed, among them abiraterone, which acts in the blockade of the enzyme 17-? dehydrogenase-hydroxysteroid and the enzyme that acts directly on the androgen receptors. A systematic review was made of studies evaluating the efficacy and safety of abiraterone plus prednisone and of enzyme adduct in patients with CPMRC both before and after docetaxel treatment. Methods: The literature search was prepared in March 2016 based on Pubmed, Google Scholar and ClinicalTrials.gov. The following search terms were used \"prostate cancer metastatic resistant\", \"prostate cancer\", \"abiraterone\" and \"enzyme\", restricted to phase III, double blind and multicenter clinical trials published in English, Spanish, Italian and Portuguese. The selected studies were analyze by LRM and AAN. The criteria for analysis were overall survival (OS), progression-free survival (PSA) and time to PSA progression (PS PSA), before and after docetaxel use. Results: Fifty-three studies were identified and, according to the inclusion criteria, four studies were selected that together added a population of 5,199 (2,394 patients after docetaxel and 2,805 patients prior to docetaxel use). In relation to SG, abiraterone reduced the risk of death by 26% after docetaxel (HR 0.74 95% CI 0.64-0.86) and 19% in predocetaxel (HR 0.81 95% CI 0.70- 0.93), and enzyme reductase reduced by 37% (HR 0.63 95% CI, 0.53-0.75) and 23% in pre docetaxel (HR 0.77 95% CI 0.67-0, 88). In relation to SLPr abiraterone delayed disease progression by 34% (HR 0.66 95% CI 0.58-0.76) and 48% in pre-chemotherapy (HR 0.52 95% CI 0.45-0, 61), and enzyme-alpha 60% after chemo (HR 0.40 95% CI 0.35-0.47) and 68% in pre-chemo (HR 0.32 95% CI 0.28-0.36). Abiraterone increased the time until PSA progression by 64% after chemo (HR 0.36 95% CI 0.52-0.78) and 50% in pre-chemo (HR 0.50 95% CI 0.43-0, 58), and enzyme-alpha in 75% after chemo (HR 0.25 95% CI 0.20-0.30) and 83% in pre-chemo (HR 0.17 95% CI 0.15-0.20). Conclusion: Both abiraterone and enzalutamide showed better results in increasing SG, SLPr and TP PSA in the treatment of patients with CPMRC. There is no direct comparative study and, because of differences in inclusion criteria and comparator groups between these clinical studies, indirect analysis of such drugs is not possible. Thus, questions such as the best pre and post chemo treatment strategy and the optimal sequencing for CPMRC coping cannot be answered.

Introdução: O câncer de próstata metastático resistente à castração apresenta sobrevida inferior a 30% em cinco anos, e o único tratamento disponível para os pacientes até pouco tempo atrás era o docetaxel. Com o maior entendimento dos mecanismos de resistência desse câncer às terapias utilizadas, novas drogas foram desenvolvidas, entre elas a abiraterona, que atua no bloqueio da enzima 17-? desidrogenase-hidroxiesteroide e a enzalutamida que age diretamente nos receptores de androgênios. Foi realizada uma revisão sistemática dos estudos que avaliaram a eficácia e segurança da abiraterona mais prednisona e da enzalutamida em pacientes com CPMRC, tanto previamente quanto posteriormente ao tratamento com docetaxel. Métodos: A pesquisa bibliográfica foi realizada em março de 2016 nas bases da Pubmed, Google Acadêmico e ClinicalTrials.gov. Os seguintes termos de pesquisa foram utilizados \"prostate cancer metastatic resistent\", \"prostate cancer\", \"abiraterone\" e enzalutamide\", restringido a estudos clínicos randomizados fase III, duplo cego e multicêntrico, publicados nos idiomas inglês, espanhol. Os estudos selecionados foram analisados de forma independente por LRM e AAN. Os critérios para análise foram a sobrevida global (SG), sobrevida livre de progressão (SLP) e o tempo até a progressão do PSA (TP PSA), previamente e após o uso de docetaxel. Resultados: Foram identificados 53 estudos. Aplicando os critérios de inclusão foram selecionados quatro estudos que juntos somaram uma população de 5.199 (2.394 pacientes após docetaxel e 2.805 pacientes previamente ao uso do docetaxel). Em relação a SG, a abiraterona reduziu o risco de morte em 26% após docetaxel (HR 0,74 95% IC 0,64-0,86) e 19% no pré-docetaxel (HR 0,81 95% IC 0,70-0,93), e a enzalutamida reduziu em 37% após (HR 0,63 95% IC, 0,53-0,75) e 23% no pré-docetaxel (HR 0,77 95% IC 0,67-0,88). Em relação a SLPr, abiraterona retardou a progressão da doença em 34% após (HR 0,66 95% IC 0,58-0,76) e 48% na pré-quimio (HR 0,52 95% IC 0,45-0,61), e a enzalutamida em 60% após quimio (HR 0,40 95% IC 0,35-0,47) e 68% na pré-quimio (HR 0,32 95% IC 0,28-0,36). Abiraterona aumentou o tempo até a progressão do PSA em 64% após quimio (HR 0,36 95% IC 0,52-0,78) e 50% na pré-quimio (HR 0,50 95% IC 0,43- 0,58), e a enzalutamida em 75% após quimio (HR 0,25 95% IC 0,20-0,30) e 83% na pré- quimio (HR 0,17 95% IC 0,15-0,20). Conclusão: Tanto abiraterona quanto enzalutamida demonstraram melhores resultados no aumento da SG, da SLPr e do TP PSA no tratamento de pacientes com CPMRC. Não há um estudo comparativo direto e devido a diferenças nos critérios de inclusão e dos grupos comparadores entre esses estudos clínicos, não é possível uma análise indireta entre tais medicamentos. Assim, questões como qual a melhor estratégia de tratamento na pré e pós-quimio e o sequenciamento ideal para enfrentamento do CPMRC não podem ser respondidas. / Introduction: Castrate-resistant metastatic prostate cancer presents survival less than 30% in five years, and the only treatment available to patients until recently was docetaxel. With the greater understanding of the mechanisms of resistance of this cancer to the therapies used, new drugs have been developed, among them abiraterone, which acts in the blockade of the enzyme 17-? dehydrogenase-hydroxysteroid and the enzyme that acts directly on the androgen receptors. A systematic review was made of studies evaluating the efficacy and safety of abiraterone plus prednisone and of enzyme adduct in patients with CPMRC both before and after docetaxel treatment. Methods: The literature search was prepared in March 2016 based on Pubmed, Google Scholar and ClinicalTrials.gov. The following search terms were used \"prostate cancer metastatic resistant\", \"prostate cancer\", \"abiraterone\" and \"enzyme\", restricted to phase III, double blind and multicenter clinical trials published in English, Spanish, Italian and Portuguese. The selected studies were analyze by LRM and AAN. The criteria for analysis were overall survival (OS), progression-free survival (PSA) and time to PSA progression (PS PSA), before and after docetaxel use. Results: Fifty-three studies were identified and, according to the inclusion criteria, four studies were selected that together added a population of 5,199 (2,394 patients after docetaxel and 2,805 patients prior to docetaxel use). In relation to SG, abiraterone reduced the risk of death by 26% after docetaxel (HR 0.74 95% CI 0.64-0.86) and 19% in predocetaxel (HR 0.81 95% CI 0.70- 0.93), and enzyme reductase reduced by 37% (HR 0.63 95% CI, 0.53-0.75) and 23% in pre docetaxel (HR 0.77 95% CI 0.67-0, 88). In relation to SLPr abiraterone delayed disease progression by 34% (HR 0.66 95% CI 0.58-0.76) and 48% in pre-chemotherapy (HR 0.52 95% CI 0.45-0, 61), and enzyme-alpha 60% after chemo (HR 0.40 95% CI 0.35-0.47) and 68% in pre-chemo (HR 0.32 95% CI 0.28-0.36). Abiraterone increased the time until PSA progression by 64% after chemo (HR 0.36 95% CI 0.52-0.78) and 50% in pre-chemo (HR 0.50 95% CI 0.43-0, 58), and enzyme-alpha in 75% after chemo (HR 0.25 95% CI 0.20-0.30) and 83% in pre-chemo (HR 0.17 95% CI 0.15-0.20). Conclusion: Both abiraterone and enzalutamide showed better results in increasing SG, SLPr and TP PSA in the treatment of patients with CPMRC. There is no direct comparative study and, because of differences in inclusion criteria and comparator groups between these clinical studies, indirect analysis of such drugs is not possible. Thus, questions such as the best pre and post chemo treatment strategy and the optimal sequencing for CPMRC coping cannot be answered.

<p><a>Prostate cancer is the second leading cause of cancer death among men in the United States. The androgen receptor (AR) antagonist enzalutamide is an FDA-approved drug for treatment of patients with late-stage prostate cancer and is currently under clinical study for early-stage prostate cancer treatment.</a> After a short positive response period to enzalutamide, tumors will develop drug resistance. In these studies, we uncovered that NOTCH signaling and DNA methylation are a deregulated in enzalutamide-resistant cells. <i>NOTCH2</i> and<i> c-MYC </i><a>gene expression<i> </i>positively correlated with <i>AR </i>expression in samples from patients with hormone refractory disease in which AR expression levels correspond to those typically observed in enzalutamide-resistance</a>. The expression of Notch signaling components was upregulated in enzalutamide-resistant cells suggesting the activation of the pathway. Inhibition of this pathway <i>in vitro</i> and <i>in vivo</i> promoted an increase in the sensitivity to enzalutamide with an impact on AR expression. On the other hand, DNMT activity and DNMT3B expression were upregulated in resistant lines. Enzalutamide induced the expression of DNMT3A and DNMT3B in prostate cancer cells with a potential role for p53 and pRB in this process. The overexpression of DNMT3B3, a DNMT3B variant, promoted an enzalutamide-resistant phenotype in C4-2 cells. DNA methylation inhibition, using low-concentration decitabine, and <i>DNMT3B</i> knockdown induced a re-sensitization of resistant prostate cancer cells and tumors to enzalutamide. Decitabine treatment in enzalutamide-resistant induced a decrease in the expression of AR-V7 and changes in genes from the apoptosis, DNA repair and mRNA splicing pathways. Decitabine plus enzalutamide treatment of 22RV1 xenografts induced a decrease in tumor weight, KI-67 and AR-V7 expression and an increase in Cleaved-Caspase3 levels. All the above suggest that Notch signaling and DNA methylation pathways are deregulated after enzalutamide resistance onset, and targeting these pathways restores the sensitivity to enzalutamide.<b><u></u></b></p>

<p>  </p> <p><strong>ABSTRACT</strong></p> <p>The worldwide obesity prevalence has almost tripled since 1973 according to the World Health Organization. In the United States, the disease is especially prevalent, with a recorded prevalence of 41.9 percent in 2017, as reported by the National Health and Nutrition Examination Survey. Obesity is associated with an increased risk of heart disease, type 2 diabetes, stroke, non-alcoholic fatty liver disease (NAFLD), and certain types of cancers, including prostate cancer (PCa). While obesity is preventable and reversible, it is a relapsing disease that requires long-term intervention. Furthermore, accumulating evidence shows obesity is not simply a matter of lack of willpower but the re-wired and altered biology that may need medical treatment. Therefore, researchers have been searching for effective approaches to treat obesity and obesity-related diseases. To this end, my research focuses on exploring the role of the sterol O-acyltransferase (SOAT) enzyme and how the inhibition of the enzyme benefits the treatment of obesity and PCa. In addition, I also studied the molecular signatures of NAFLD, with a special focus on altered lipid metabolism using proteomics and determined the protein oligomerization profiles. The major lines of research are summarized in the following and discussed in greater detail in chapters 2 to 5. </p> <p>SOAT enzyme catalyzes the conversion of free cholesterol into its storage form, cholesteryl ester. Our group previously showed that increased SOAT1 expression is associated with increased adipogenesis <em>in vitro</em> and increased adiposity in adipose tissue. When SOAT1 activity was blocked using the pharmacological inhibitor avasimibe, lipid droplet formation and expansion during adipogenesis were suppressed. We further showed that non-orally administered avasimibe led to significant fat mass loss in diet-induced obese (DIO) mice with concomitant food intake suppression and decreased expression of lipogenic genes in adipose tissue. Based on the promising use of avasimibe as an anti-obesity medication, I sought to answer whether avasimibe can enhance the weight loss effect of glucagon-like peptide-1 receptor agonist (GLP-1RA) by accelerating fat mass loss (chapter 2). We found subcutaneous administration of avasimibe can significantly potentiate the weight-reducing effect of the GLP-1RA in DIO mice.</p> <p>Inspired by the lipid droplet modulatory role of the SOAT1 enzyme, I also expanded my dissertation project to cancer (chapter 3). I found that low SOAT1 expression is associated with favorable patient outcomes among PCa patients who had previously undergone anti-hormone therapy. Since the current treatment option, anti-androgen drug enzalutamide, induces mechanisms of resistance in a short period, I hypothesized that blockage of SOAT1 activity using avasimibe would enhance the enzalutamide action and help overcome the resistance. To test this hypothesis, I characterized lipidomic signatures of PCa cells in response to enzalutamide and avasimibe treatments. Then, I tested the anti-cancer effect of the combined treatment in cell cultures and in xenograft tumors in nude mice. I found the combined treatment was significantly more effective in inhibiting cancer cell proliferation and tumor growth than each drug treatment alone. These findings provide insights into molecular signatures associated with enzalutamide treatment outcomes and can serve as a prelude to developing a therapeutic regimen targeting cholesterol metabolism. </p> <p>Among the comorbidities of obesity, NAFLD is very common in obese adults and the prevalence is close to 50–90%. We launched the third project (chapter 4) where we compared the liver proteome from lean mice and DIO mice. To date, most of the omics studies on DIO have been monolithic and very few have explored the multi-omic aspects of fatty liver tissue. To address this gap, we integrated global proteomics, phosphoproteomics and lipidomics to determine molecular signatures of the fatty liver. We identified a range of biological pathways that were altered, and we showed how the alterations in lipid content and amount were correlated with the alterations in the liver proteome and phosphoproteome. The results shed light on the interrelated nature of these biological processes. This was hypothesis-generating study that provided extensive data that could guide future investigations. </p> <p>We followed up on the third project and employed extensive measures to determine the protein oligomerization profiles of the fatty liver (chapter 5). Understanding the modes of protein oligomerization is important since proteins typically exert their biological functions by interacting with other proteins to form protein complexes. We used size exclusion chromatography (SEC) to fractionate liver proteins into 32 fractions based on their size and conducted label-free quantitation of each fraction using mass spectrometry. We successfully obtained elution profiles of individual proteins for subsequent comparison. Our approach enabled the identification of 1172 proteins found common in four liver samples (two lean livers and two fatty livers) for correlation profiling. We discovered that protein elution profiles were highly conserved in the fatty livers despite the metabolic disease state. At the same time, we identified several proteins with different elution profiles between the lean and the fatty livers, which could potentially mediate the hepatic dysfunctions displayed in NAFLD. This study delivers novel pieces of information about protein complex formation in fatty livers.</p> <p>The four research projects included in this dissertation explored obesity and obesity related diseases. Cholesterol accumulation is manifested as lipid metabolism is altered during the progression of obesity in adipose tissue and in PCa. Pharmacological inhibition of SOAT is responsible for cholesterol accumulation was effective in weight management in DIO and demonstrated anti-cancer effect in PCa models together with enzalutamide. These findings suggest that SOAT could be a therapeutic target for diseases featuring cholesteryl ester accumulation. Subsequent projects explored the liver proteome and revealed. In the subsequent projects, liver proteome showed a clear distinction between lean mice and obese mice. The identified proteins in these studies could facilitate the development of targeted therapies for treating NAFLD.</p>

La sénescence cellulaire est un mécanisme naturel de suppression tumorale défini par un arrêt stable de la prolifération. Bien que presque toujours mutées dans au moins une des voies déclenchant la sénescence (ex : p53/p21 ou p16/Rb), les cellules cancéreuses conservent souvent la capacité d’y entrer en réponse au traitement. Cette sénescence induite par la thérapie (SIT) peut être ciblée pharmacologiquement pour en renforcer les effets positifs. Une approche émergente consiste à combiner un traitement anticancéreux induisant la sénescence à un sénolytique, agent éliminant spécifiquement les cellules sénescentes. Dans le contexte du cancer de la prostate (CP), différents types de SIT ont déjà été observées dans de multiples modèles exposés à différents traitements. Cependant, le manque de données comparant ces phénotypes souligne le besoin d’analyses plus systématiques. De plus, la sensibilité aux sénolytiques des cellules du CP en état de SIT n’a pas encore été évaluée dans ces contextes. Dans cette étude, nous avons évalué les destins cellulaires des lignées du CP après exposition à trois traitements pertinents au niveau clinique : l’irradiation et l’olaparib, deux inducteurs de dommages à l’ADN et l’enzalutamide, un anti-androgène. Dépendamment de la lignée, les traitements par irradiation et olaparib ont mené à une réponse dirigée principalement vers la sénescence ou vers une réponse mixte de mort cellulaire, de catastrophe mitotique et de sénescence. Dans tous les cas, ceux-ci ont déclenché un phénotype sénescent classique et convertible en mort cellulaire par des sénolytiques inhibiteurs des antiapoptotiques de la famille Bcl-2. D’autre part, le traitement à l’enzalutamide a déclenché un phénotype semblable à la sénescence se distinguant par sa réversibilité, son absence de dommages à l’ADN et son insensibilité à ces mêmes sénolytiques. Globalement, nos résultats soulignent l’importance du contexte thérapeutique dans l’élaboration des stratégies de manipulation de la SIT du CP. Ils constituent également une justification robuste à l’étude préclinique des traitements combinant la radiothérapie ou l’olaparib à des inhibiteurs des antiapoptotiques de la famille Bcl-2 dans le contexte du CP. / Cellular senescence is a natural tumor suppression mechanism defined by a stable proliferation arrest. Although almost always mutated in at least one of the senescence pathways genes (e.g., p53/p21 or p16/Rb), cancer cells often retain the ability to become senescent in response to treatment. This therapy-induced senescence (TIS) can be pharmacologically targeted to enhance its positive effects. An emerging approach is to combine senescence-inducing cancer treatment with senolytics, compounds that specifically eliminate senescent cells. In the context of prostate cancer (PCa), different types of TIS have already been observed in multiple models exposed to different treatments. However, the lack of data comparing these phenotypes highlights the need for more systematic analyses. In addition, the senolytic sensitivity of TIS PCa cells has not yet been evaluated in these settings. In this study, we evaluated the cell fates of PCa cell lines after exposure to three clinically relevant treatments: irradiation and olaparib, two DNA damage inducers, and enzalutamide, an anti-androgen. Depending on the cell line, irradiation and olaparib treatments led to a response mainly directed towards senescence or toward a mixed response of cell death, mitotic catastrophe and senescence. In all cases, these treatments triggered a classic senescent phenotype that was convertible to cell death by senolytic inhibitors of the Bcl-2 family antiapoptotics. On the other hand, treatment with enzalutamide triggered a senescence-like phenotype, distinguishable by its reversibility, absence of DNA damage and insensitivity to these same senolytics. Overall, our results underscore the importance of the therapeutic context in the development of PCa-TIS manipulation strategies. They also provide a robust rationale for the preclinical study of treatments that combine radiotherapy or olaparib with Bcl-2 family antiapoptotic inhibitors in the PCa context.

No description available.