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Most children with medulloblastoma (MB) achieve remission, but some face very aggressive metastatic tumors. Their dismal outcome highlights the critical need to advance therapeutic approaches that benefit such high-risk patients. Minnelide, a clinically relevant analog of the natural product triptolide, has oncostatic activity in both preclinical and early clinical settings. Despite its efficacy and tolerable toxicity, this compound has not been evaluated in MB. Utilizing a bioinformatic data set that integrates cellular drug response data with gene expression, we predicted that Group 3 (G3) MB, which has a poor 5-year survival, would be sensitive to triptolide/Minnelide. We subsequently showed that both triptolide and Minnelide attenuate the viability of G3 MB cells ex vivo. Transcriptomic analyses identified MYC signaling, a pathologically relevant driver of G3 MB, as a downstream target of this class of drugs. We validated this MYC dependency in G3 MB cells and showed that triptolide exerts its efficacy by reducing both MYC transcription and MYC protein stability. Importantly, Minnelide acted on MYC to reduce tumor growth and leptomeningeal spread, which resulted in improved survival of G3 MB animal models. Moreover, Minnelide improved the efficacy of adjuvant chemotherapy, further highlighting its potential for the treatment of MYC-driven G3 MB.
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Diterpenos , Compuestos Epoxi , Meduloblastoma , Fenantrenos , Proteínas Proto-Oncogénicas c-myc , Ensayos Antitumor por Modelo de Xenoinjerto , Fenantrenos/farmacología , Diterpenos/farmacología , Compuestos Epoxi/farmacología , Meduloblastoma/tratamiento farmacológico , Meduloblastoma/genética , Meduloblastoma/patología , Meduloblastoma/metabolismo , Animales , Humanos , Ratones , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Línea Celular Tumoral , Profármacos/farmacología , Neoplasias Cerebelosas/tratamiento farmacológico , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/patología , Neoplasias Cerebelosas/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , OrganofosfatosRESUMEN
Pediatric brain tumors are the leading cause of cancer-related deaths in children, with medulloblastoma (MB) being the most common type. A better understanding of these malignancies has led to their classification into four major molecular subgroups. This classification not only facilitates the stratification of clinical trials, but also the development of more effective therapies. Despite recent progress, approximately 30% of children diagnosed with MB experience tumor relapse. Recurrent disease in MB is often metastatic and responds poorly to current therapies. As a result, only a small subset of patients with recurrent MB survive beyond one year. Due to its dismal prognosis, novel therapeutic strategies aimed at preventing or managing recurrent disease are urgently needed. In this review, we summarize recent advances in our understanding of the molecular mechanisms behind treatment failure in MB, as well as those characterizing recurrent cases. We also propose avenues for how these findings can be used to better inform personalized medicine approaches for the treatment of newly diagnosed and recurrent MB. Lastly, we discuss the treatments currently being evaluated for MB patients, with special emphasis on those targeting MB by subgroup at diagnosis and relapse.
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Neoplasias Cerebelosas , Meduloblastoma , Recurrencia Local de Neoplasia , Humanos , Meduloblastoma/patología , Meduloblastoma/genética , Meduloblastoma/terapia , Meduloblastoma/tratamiento farmacológico , Neoplasias Cerebelosas/patología , Neoplasias Cerebelosas/tratamiento farmacológico , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/terapia , Animales , Niño , Antineoplásicos/uso terapéutico , Medicina de PrecisiónRESUMEN
Pancreatic ductal adenocarcinoma (PDAC), the most prevalent type of pancreatic cancer, is one of the deadliest forms of cancer with limited therapy options. Overexpression of the heat shock protein 70 (HSP70) is a hallmark of cancer that is strongly associated with aggressive disease and worse clinical outcomes. However, the underlying mechanisms by which HSP70 allows tumor cells to thrive under conditions of continuous stress have not been fully described. Here, we report that PDAC has the highest expression of HSP70 relative to normal tissue across all cancers analyzed. Furthermore, HSP70 expression is associated with tumor grade and is further enhanced in metastatic PDAC. We show that genetic or therapeutic ablation of HSP70 alters mitochondrial subcellular localization, impairs mitochondrial dynamics, and promotes mitochondrial swelling to induce apoptosis. Mechanistically, we find that targeting HSP70 suppresses the PTEN-induced kinase 1 (PINK1) mediated phosphorylation of dynamin-related protein 1 (DRP1). Treatment with the HSP70 inhibitor AP-4-139B was efficacious as a single agent in primary and metastatic mouse models of PDAC. In addition, we demonstrate that HSP70 inhibition promotes the AMP-activated protein kinase (AMPK) mediated phosphorylation of Beclin-1, a key regulator of autophagic flux. Accordingly, we find that the autophagy inhibitor hydroxychloroquine (HCQ) enhances the ability of AP-4-139B to mediate anti-tumor activity in vivo. Collectively, our results suggest that HSP70 is a multi-functional driver of tumorigenesis that orchestrates mitochondrial dynamics and autophagy. Moreover, these findings support the rationale for concurrent inhibition of HSP70 and autophagy as a novel therapeutic approach for HSP70-driven PDAC.
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Autofagia , Carcinoma Ductal Pancreático , Proteínas HSP70 de Choque Térmico , Dinámicas Mitocondriales , Neoplasias Pancreáticas , Dinámicas Mitocondriales/efectos de los fármacos , Proteínas HSP70 de Choque Térmico/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/tratamiento farmacológico , Autofagia/efectos de los fármacos , Humanos , Animales , Ratones , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/tratamiento farmacológico , Línea Celular Tumoral , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Proteínas Quinasas/metabolismoRESUMEN
The tumor suppressor TP53 is the most frequently mutated gene in cancer and is mutationally inactivated in 50% of sporadic tumors. Inactivating mutations in TP53 also occur in Li Fraumeni syndrome (LFS). In addition to germline mutations in TP53 in LFS that completely inactivate this protein, there are many more germline mutant forms of TP53 in human populations that partially inactivate this protein: we call these partially inactivating mutations "hypomorphs." One of these hypomorphs is a SNP that exists in 6%-10% of Africans and 1%-2% of African Americans, which changes proline at amino acid 47 to serine (Pro47Ser; P47S). We previously showed that the P47S variant of p53 is intrinsically impaired for tumor suppressor function, and that this SNP is associated with increased cancer risk in mice and humans. Here we show that this SNP also influences the tumor microenvironment, and the immune microenvironment profile in P47S mice is more protumorigenic. At basal levels, P47S mice show impaired memory T-cell formation and function, along with increased anti-inflammatory (so-called "M2") macrophages. We show that in tumor-bearing P47S mice, there is an increase in immunosuppressive myeloid-derived suppressor cells and decreased numbers of activated dendritic cells, macrophages, and B cells, along with evidence for increased T-cell exhaustion in the tumor microenvironment. Finally, we show that P47S mice demonstrate an incomplete response to anti-PD-L1 therapy. Our combined data suggest that the African-centric P47S variant leads to both intrinsic and extrinsic defects in tumor suppression. Significance: Findings presented here show that the P47S variant of TP53 influences the immune microenvironment, and the immune response to cancer. This is the first time that a naturally occurring genetic variant of TP53 has been shown to negatively impact the immune microenvironment and the response to immunotherapy.
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Síndrome de Li-Fraumeni , Proteína p53 Supresora de Tumor , Humanos , Ratones , Animales , Proteína p53 Supresora de Tumor/genética , Inhibidores de Puntos de Control Inmunológico , Síndrome de Li-Fraumeni/genética , Genes p53 , Mutación de Línea Germinal , Microambiente Tumoral/genéticaRESUMEN
TP53 is the most frequently mutated gene in cancer, yet key target genes for p53-mediated tumor suppression remain unidentified. Here, we characterize a rare, African-specific germline variant of TP53 in the DNA-binding domain Tyr107His (Y107H). Nuclear magnetic resonance and crystal structures reveal that Y107H is structurally similar to wild-type p53. Consistent with this, we find that Y107H can suppress tumor colony formation and is impaired for the transactivation of only a small subset of p53 target genes; this includes the epigenetic modifier PADI4, which deiminates arginine to the nonnatural amino acid citrulline. Surprisingly, we show that Y107H mice develop spontaneous cancers and metastases and that Y107H shows impaired tumor suppression in two other models. We show that PADI4 is itself tumor suppressive and that it requires an intact immune system for tumor suppression. We identify a p53-PADI4 gene signature that is predictive of survival and the efficacy of immune-checkpoint inhibitors. SIGNIFICANCE: We analyze the African-centric Y107H hypomorphic variant and show that it confers increased cancer risk; we use Y107H in order to identify PADI4 as a key tumor-suppressive p53 target gene that contributes to an immune modulation signature and that is predictive of cancer survival and the success of immunotherapy. See related commentary by Bhatta and Cooks, p. 1518. This article is highlighted in the In This Issue feature, p. 1501.
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Genes p53 , Neoplasias , Proteína p53 Supresora de Tumor , Animales , Humanos , Ratones , Pueblo Africano/genética , Neoplasias/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Although many therapeutic options are available, several factors, including the presence of p53 mutations, impact tumor development and therapeutic resistance. TP53 is the second most frequently mutated gene in HCC, comprising more than 30% of cases. Mutations in p53 result in the formation of amyloid aggregates that promote tumor progression. The use of PRIMA-1, a small molecule capable of restoring p53, is a therapeutic strategy to pharmacologically target the amyloid state mutant p53. In this study, we characterize an HCC mutant p53 model for the study of p53 amyloid aggregation in HCC cell lines, from in silico analysis of p53 mutants to a 3D-cell culture model and demonstrate the unprecedented inhibition of Y220C mutant p53 aggregation by PRIMA-1. In addition, our data show beneficial effects of PRIMA-1 in several "gain of function" properties of mutant-p53 cancer cells, including migration, adhesion, proliferation, and drug resistance. We also demonstrate that the combination of PRIMA-1 and cisplatin is a promising approach for HCC therapy. Taken together, our data support the premise that targeting the amyloid-state of mutant p53 may be an attractive therapeutic approach for HCC, and highlight PRIMA-1 as a new candidate for combination therapy with cisplatin.
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Missense mutations that inactivate p53 occur commonly in cancer, and germline mutations in TP53 cause Li Fraumeni syndrome, which is associated with early-onset cancer. In addition, there are over two hundred germline missense variants of p53 that remain uncharacterized. In some cases, these germline variants have been shown to encode lesser-functioning, or hypomorphic, p53 protein, and these alleles are associated with increased cancer risk in humans and mouse models. However, most hypomorphic p53 variants remain un- or mis-classified in clinical genetics databases. There thus exists a significant need to better understand the behavior of p53 hypomorphs and to develop a functional assay that can distinguish hypomorphs from wild-type p53 or benign variants. We report the surprising finding that two different African-centric genetic hypomorphs of p53 that occur in distinct functional domains of the protein share common activities. Specifically, the Pro47Ser variant, located in the transactivation domain, and the Tyr107His variant, located in the DNA binding domain, both share increased propensity to misfold into a conformation specific for mutant, misfolded p53. Additionally, cells and tissues containing these hypomorphic variants show increased NF-κB activity. We identify a common gene expression signature from unstressed lymphocyte cell lines that is shared between multiple germline hypomorphic variants of TP53, and which successfully distinguishes wild-type p53 and a benign variant from lesser-functioning hypomorphic p53 variants. Our findings will allow us to better understand the contribution of p53 hypomorphs to disease risk and should help better inform cancer risk in the carriers of p53 variants.
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Síndrome de Li-Fraumeni , Proteína p53 Supresora de Tumor , Animales , Ratones , Humanos , Proteína p53 Supresora de Tumor/metabolismo , Predisposición Genética a la Enfermedad , Síndrome de Li-Fraumeni/genética , Genes p53 , Heterocigoto , Mutación de Línea GerminalRESUMEN
The TP53 gene continues to hold distinction as the most frequently mutated gene in cancer. Since its discovery in 1979, hundreds of research groups have devoted their efforts toward understanding why this gene is so frequently selected against by tumors, with the hopes of harnessing this information toward the improved therapy of cancer. The result is that this protein has been meticulously analyzed in tumor and normal cells, resulting in over 100,000 publications, with an average of 5000 papers published on p53 every year for the past decade. The journey toward understanding p53 function has been anything but straightforward; in fact, the field is notable for the numerous times that established paradigms not only have been shifted, but in fact have been shattered or reversed. In this review, we will discuss the manuscripts, or series of manuscripts, that have most radically changed our thinking about how this tumor suppressor functions, and we will delve into the emerging challenges for the future in this important area of research. It is hoped that this review will serve as a useful historical reference for those interested in p53, and a useful lesson on the need to be flexible in the face of established paradigms.
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Genes p53/genética , Neoplasias/genética , Proteína p53 Supresora de Tumor/genética , Animales , Humanos , Mutación/genéticaRESUMEN
NRAS-mutant melanoma is currently a challenge to treat. This is due to an absence of inhibitors directed against mutant NRAS, along with adaptive and acquired resistance of this tumor type to inhibitors in the MAPK pathway. Inhibitors to MEK (mitogen-activated protein kinase kinase) have shown some promise for NRAS-mutant melanoma. In this work we explored the use of MEK inhibitors for NRAS-mutant melanoma. At the same time we investigated the impact of the brain microenvironment, specifically astrocytes, on the response of a melanoma brain metastatic cell line to MEK inhibition. These parallel avenues led to the surprising finding that astrocytes enhance the sensitivity of melanoma tumors to MEK inhibitors (MEKi). We show that MEKi cause an upregulation of the transcription factor ID3, which confers resistance. This upregulation of ID3 is blocked by conditioned media from astrocytes. We show that silencing ID3 enhances the sensitivity of melanoma to MEK inhibitors, thus mimicking the effect of the brain microenvironment. Moreover, we report that ID3 is a client protein of the chaperone HSP70, and that HSP70 inhibition causes ID3 to misfold and accumulate in a detergent-insoluble fraction in cells. We show that HSP70 inhibitors synergize with MEK inhibitors against NRAS-mutant melanoma, and that this combination significantly enhances the survival of mice in two different models of NRAS-mutant melanoma. These studies highlight ID3 as a mediator of adaptive resistance, and support the combined use of MEK and HSP70 inhibitors for the therapy of NRAS-mutant melanoma. SIGNIFICANCE: MEK inhibitors are currently used for NRAS-mutant melanoma, but have shown modest efficacy as single agents. This research shows a synergistic effect of combining HSP70 inhibitors with MEK inhibitors for the treatment of NRAS mutant melanoma.
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Melanoma , Quinasas de Proteína Quinasa Activadas por Mitógenos , Ratones , Animales , GTP Fosfohidrolasas/genética , Proteínas de la Membrana/genética , Mutación , Melanoma/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Microambiente TumoralRESUMEN
The Pro47Ser variant of p53 (S47) exists in African-descent populations and is associated with increased cancer risk in humans and mice. Due to impaired repression of the cystine importer Slc7a11, S47 cells show increased glutathione (GSH) accumulation compared to cells with wild -type p53. We show that mice containing the S47 variant display increased mTOR activity and oxidative metabolism, as well as larger size, improved metabolic efficiency, and signs of superior fitness. Mechanistically, we show that mTOR and its positive regulator Rheb display increased association in S47 cells; this is due to an altered redox state of GAPDH in S47 cells that inhibits its ability to bind and sequester Rheb. Compounds that decrease glutathione normalize GAPDH-Rheb complexes and mTOR activity in S47 cells. This study reveals a novel layer of regulation of mTOR by p53, and raises the possibility that this variant may have been selected for in early Africa.
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Serina-Treonina Quinasas TOR/metabolismo , Proteína p53 Supresora de Tumor/genética , Sustitución de Aminoácidos/genética , Animales , Población Negra/genética , Línea Celular , Glutatión/metabolismo , Glucólisis , Humanos , Mitocondrias/metabolismo , Oxidación-Reducción , Serina-Treonina Quinasas TOR/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
The protein chaperone HSP70 is overexpressed in many cancers including colorectal cancer, where overexpression is associated with poor survival. We report here the creation of a uniquely acting HSP70 inhibitor (HSP70i) that targets multiple compartments in the cancer cell, including mitochondria. This inhibitor was mitochondria toxic and cytotoxic to colorectal cancer cells, but not to normal colon epithelial cells. Inhibition of HSP70 was efficacious as a single agent in primary and metastatic models of colorectal cancer and enabled identification of novel mitochondrial client proteins for HSP70. In a syngeneic colorectal cancer model, the inhibitor increased immune cell recruitment into tumors. Cells treated with the inhibitor secreted danger-associated molecular patterns (DAMP), including ATP and HMGB1, and functioned effectively as a tumor vaccine. Interestingly, the unique properties of this HSP70i in the disruption of mitochondrial function and the inhibition of proteostasis both contributed to DAMP release. This HSP70i constitutes a promising therapeutic opportunity in colorectal cancer and may exhibit antitumor activity against other tumor types. SIGNIFICANCE: These findings describe a novel HSP70i that disrupts mitochondrial proteostasis, demonstrating single-agent efficacy that induces immunogenic cell death in treated tumors.
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Antineoplásicos/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Proteínas HSP70 de Choque Térmico/antagonistas & inhibidores , Mitocondrias/efectos de los fármacos , Adenosina Trifosfato/metabolismo , Alarminas/metabolismo , Animales , Sistema Libre de Células , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Proteína HMGB1/metabolismo , Células HT29 , Ensayos Analíticos de Alto Rendimiento , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Mitocondrias/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Germline mutations in TP53 cause a rare high penetrance cancer syndrome, Li-Fraumeni syndrome (LFS). Here, we identified a rare TP53 tetramerization domain missense mutation, c.1000G>C;p.G334R, in a family with multiple late-onset LFS-spectrum cancers. Twenty additional c.1000G>C probands and one c.1000G>A proband were identified, and available tumors showed biallelic somatic inactivation of TP53. The majority of families were of Ashkenazi Jewish descent, and the TP53 c.1000G>C allele was found on a commonly inherited chromosome 17p13.1 haplotype. Transient transfection of the p.G334R allele conferred a mild defect in colony suppression assays. Lymphoblastoid cell lines from the index family in comparison with TP53 normal lines showed that although classical p53 target gene activation was maintained, a subset of p53 target genes (including PCLO, PLTP, PLXNB3, and LCN15) showed defective transactivation when treated with Nutlin-3a. Structural analysis demonstrated thermal instability of the G334R-mutant tetramer, and the G334R-mutant protein showed increased preponderance of mutant conformation. Clinical case review in comparison with classic LFS cohorts demonstrated similar rates of pediatric adrenocortical tumors and other LFS component cancers, but the latter at significantly later ages of onset. Our data show that TP53 c.1000G>C;p.G334R is found predominantly in Ashkenazi Jewish individuals, causes a mild defect in p53 function, and leads to low penetrance LFS. SIGNIFICANCE: TP53 c.1000C>G;p.G334R is a pathogenic, Ashkenazi Jewish-predominant mutation associated with a familial multiple cancer syndrome in which carriers should undergo screening and preventive measures to reduce cancer risk.
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Predisposición Genética a la Enfermedad/genética , Síndrome de Li-Fraumeni/genética , Neoplasias/genética , Proteína p53 Supresora de Tumor/genética , Adulto , Edad de Inicio , Femenino , Mutación de Línea Germinal , Humanos , Judíos , Masculino , Mutación Missense , LinajeRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
A variant at amino acid 47 in human TP53 exists predominantly in individuals of African descent. P47S human and mouse cells show increased cancer risk due to defective ferroptosis. Here, we show that this ferroptotic defect causes iron accumulation in P47S macrophages. This high iron content alters macrophage cytokine profiles, leads to higher arginase level and activity, and decreased nitric oxide synthase activity. This leads to more productive intracellular bacterial infections but is protective against malarial toxin hemozoin. Proteomics of macrophages reveal decreased liver X receptor (LXR) activation, inflammation and antibacterial defense in P47S macrophages. Both iron chelators and LXR agonists improve the response of P47S mice to bacterial infection. African Americans with elevated saturated transferrin and serum ferritin show higher prevalence of the P47S variant (OR = 1.68 (95%CI 1.07-2.65) p = 0.023), suggestive of its role in iron accumulation in humans. This altered macrophage phenotype may confer an advantage in malaria-endemic sub-Saharan Africa.
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Hierro/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , África del Sur del Sahara , Negro o Afroamericano/genética , Animales , Infecciones Bacterianas/etiología , Infecciones Bacterianas/genética , Infecciones Bacterianas/metabolismo , Ferritinas/sangre , Ferroptosis/efectos de los fármacos , Ferroptosis/genética , Ferroptosis/fisiología , Variación Genética , Hemoproteínas/toxicidad , Humanos , Listeriosis/etiología , Receptores X del Hígado/agonistas , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Malaria/genética , Malaria/metabolismo , Ratones , Ratones Transgénicos , Transferrina/metabolismoRESUMEN
The TP53 gene is well known to be the most frequently mutated gene in human cancer. In addition to mutations, there are > 20 different coding region single-nucleotide polymorphisms (SNPs) in the TP53 gene, as well as SNPs in MDM2, the negative regulator of p53. Several of these SNPs are known to alter p53 pathway function. This makes p53 rather unique among cancer-critical genes, e.g. the coding regions of other cancer-critical genes like Ha-Ras, RB, and PI3KCA do not have non-synonymous coding region SNPs that alter their function in cancer. The next frontier in p53 biology will consist of probing which of these coding region SNPs are moderately or strongly pathogenic and whether they influence cancer risk and the efficacy of cancer therapy. The challenge after that will consist of determining whether we can tailor chemotherapy to correct the defects for each of these variants. Here we review the SNPs in TP53 and MDM2 that show the most significant impact on cancer and other diseases. We also propose avenues for how this information can be used to better inform personalized medicine approaches to cancer and other diseases.
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Neoplasias , Polimorfismo de Nucleótido Simple , Proteínas Proto-Oncogénicas c-mdm2 , Transducción de Señal/genética , Proteína p53 Supresora de Tumor , Animales , Genes ras , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteína de Retinoblastoma/genética , Proteína de Retinoblastoma/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Mutations in the TP53 tumor suppressor gene remain a hallmark of human cancer. In addition to mutation of TP53, single nucleotide polymorphisms (SNPs) in this gene can have a profound impact on p53 function, and can affect cancer risk as well as other p53 functions. Wild type (WT) p53 contains a proline at amino acid 47, but approximately 1% of African-Americans express a p53 allele with a serine at amino acid 47 (Pro47Ser, hereafter S47). In a mouse model for this variant, mice expressing S47 are predisposed to spontaneous cancers. The S47 variant also is associated with increased pre-menopausal breast cancer risk in African American women. We recently reported that S47 tumor cells are resistant to the majority of cytotoxic chemotherapeutic agents, but show increased sensitivity to a subset of anti-cancer agents, compared to tumors with WT p53. In this work, we report on another potentially promising therapeutic vulnerability of S47 tumors. We find that S47 tumors show decreased mitochondrial metabolism, along with increased dependency on glycolysis. S47 tumor cells also show increased sensitivity to the glycolytic poison 2-deoxy-glucose. We propose that the altered metabolism in S47 tumor cells may be yet another potentially-actionable therapeutic vulnerability to exploit in cancer-prone individuals with this genotype.
RESUMEN
The tumor suppressor TP53 is the most frequently mutated gene in human cancer and serves to restrict tumor initiation and progression. Single-nucleotide polymorphisms (SNP) in TP53 and p53 pathway genes can have a marked impact on p53 tumor suppressor function, and some have been associated with increased cancer risk and impaired response to therapy. Approximately 6% of Africans and 1% of African Americans express a p53 allele with a serine instead of proline at position 47 (Pro47Ser). This SNP impairs p53-mediated apoptosis in response to radiation and genotoxic agents and is associated with increased cancer risk in humans and in a mouse model. In this study, we compared the ability of wild-type (WT) and S47 p53 to suppress tumor development and respond to therapy. Our goal was to find therapeutic compounds that are more, not less, efficacious in S47 tumors. We identified the superior efficacy of two agents, cisplatin and BET inhibitors, on S47 tumors compared with WT. Cisplatin caused dramatic decreases in the progression of S47 tumors by activating the p53/PIN1 axis to drive the mitochondrial cell death program. These findings serve as important proof of principle that chemotherapy can be tailored to p53 genotype.Significance: A rare African-derived radioresistant p53 SNP provides proof of principle that chemotherapy can be tailored to TP53 genotype. Cancer Res; 78(19); 5694-705. ©2018 AACR.
Asunto(s)
Polimorfismo de Nucleótido Simple , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , África , Negro o Afroamericano/genética , Alelos , Animales , Apoptosis , Población Negra/genética , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Transformación Celular Neoplásica , Cisplatino/farmacología , Progresión de la Enfermedad , Fibroblastos/metabolismo , Genotipo , Humanos , Ratones , Mitocondrias/metabolismo , Mutación/efectos de los fármacos , Trasplante de Neoplasias , Farmacogenética , Medicina de Precisión , RiesgoRESUMEN
Approximately half of all human cancers contain mutations in the TP53 tumor suppressor. In addition to mutations, there are single nucleotide polymorphisms (SNPs) in TP53 that can dampen p53 function, and can increase cancer risk and decrease the efficacy of cancer therapy. Approximately 6% of Africans and 1% of African-Americans express a p53 allele with a serine instead of proline at position 47 (Pro47Ser, or S47). The S47 variant is associated with increased breast cancer risk in pre-menopausal African Americans, and in a mouse model for the S47 variant, mice are predisposed to spontaneous cancers. We recently showed that the S47 variant is impaired for p53-mediated apoptosis in response to radiation and some genotoxic agents, particularly cisplatin. Here we identify the mechanism for impaired apoptosis of S47 in response to cisplatin. We show that following cisplatin treatment, the S47 variant shows normal stabilization and serine 15 phosphorylation, but reduced ability to bind to the peptidyl prolyl isomerase PIN1, which controls the mitochondrial localization of p53. This is accompanied by impaired mitochondrial localization of S47, along with decreased induction of cleaved caspase-3. Interestingly, we show that this defect occurs only for cisplatin and not for camptothecin. These findings show that normal tissues may respond differently to genotoxic stress depending upon this TP53 genotype. These data suggest that toxicity to cisplatin may be decreased in S47 individuals, and that this compound may be a superior treatment option for these individuals.