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1.
JCI Insight ; 9(13)2024 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-38815134

RESUMEN

The nonphysiological nutrient levels found in traditional culture media have been shown to affect numerous aspects of cancer cell physiology, including how cells respond to certain therapeutic agents. Here, we comprehensively evaluated how physiological nutrient levels affect therapeutic response by performing drug screening in human plasma-like medium. We observed dramatic nutrient-dependent changes in sensitivity to a variety of FDA-approved and clinically trialed compounds, including rigosertib, an experimental cancer therapeutic that recently failed in phase III clinical trials. Mechanistically, we found that the ability of rigosertib to destabilize microtubules is strongly inhibited by the purine metabolism end product uric acid, which is uniquely abundant in humans relative to traditional in vitro and in vivo cancer models. These results demonstrate the broad and dramatic effects nutrient levels can have on drug response and how incorporation of human-specific physiological nutrient medium might help identify compounds whose efficacy could be influenced in humans.


Asunto(s)
Glicina , Sulfonas , Ácido Úrico , Humanos , Ácido Úrico/metabolismo , Glicina/farmacología , Glicina/análogos & derivados , Sulfonas/farmacología , Medios de Cultivo , Evaluación Preclínica de Medicamentos/métodos , Línea Celular Tumoral , Antineoplásicos/farmacología
2.
bioRxiv ; 2023 Jul 28.
Artículo en Inglés | MEDLINE | ID: mdl-37546939

RESUMEN

The non-physiological nutrient levels found in traditional culture media have been shown to affect numerous aspects of cancer cell physiology, including how cells respond to certain therapeutic agents. Here, we comprehensively evaluated how physiological nutrient levels impact therapeutic response by performing drug screening in human plasma-like medium (HPLM). We observed dramatic nutrient-dependent changes in sensitivity to a variety of FDA-approved and clinically trialed compounds, including rigosertib, an experimental cancer therapeutic that has recently failed in phase 3 clinical trials. Mechanistically, we found that the ability of rigosertib to destabilize microtubules is strongly inhibited by the purine metabolism waste product uric acid, which is uniquely abundant in humans relative to traditional in vitro and in vivo cancer models. Structural modelling studies suggest that uric acid interacts with the tubulin-rigosertib complex and may act as an uncompetitive inhibitor of rigosertib. These results offer a possible explanation for the failure of rigosertib in clinical trials and demonstrate the utility of physiological media to achieve in vitro results that better represent human therapeutic responses.

3.
Cancer Cell ; 40(9): 939-956.e16, 2022 09 12.
Artículo en Inglés | MEDLINE | ID: mdl-35985343

RESUMEN

Mutations affecting isocitrate dehydrogenase (IDH) enzymes are prevalent in glioma, leukemia, and other cancers. Although mutant IDH inhibitors are effective against leukemia, they seem to be less active in aggressive glioma, underscoring the need for alternative treatment strategies. Through a chemical synthetic lethality screen, we discovered that IDH1-mutant glioma cells are hypersensitive to drugs targeting enzymes in the de novo pyrimidine nucleotide synthesis pathway, including dihydroorotate dehydrogenase (DHODH). We developed a genetically engineered mouse model of mutant IDH1-driven astrocytoma and used it and multiple patient-derived models to show that the brain-penetrant DHODH inhibitor BAY 2402234 displays monotherapy efficacy against IDH-mutant gliomas. Mechanistically, this reflects an obligate dependence of glioma cells on the de novo pyrimidine synthesis pathway and mutant IDH's ability to sensitize to DNA damage upon nucleotide pool imbalance. Our work outlines a tumor-selective, biomarker-guided therapeutic strategy that is poised for clinical translation.


Asunto(s)
Neoplasias Encefálicas , Glioma , Leucemia , Animales , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Inhibidores Enzimáticos/uso terapéutico , Glioma/tratamiento farmacológico , Glioma/genética , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Ratones , Mutación , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Salicilanilidas , Triazoles
4.
Sci Signal ; 14(686)2021 06 08.
Artículo en Inglés | MEDLINE | ID: mdl-34103421

RESUMEN

Cancer cells have differential metabolic dependencies compared to their nonmalignant counterparts. However, few metabolism-targeting compounds have been successful in clinical trials. Here, we investigated the metabolic vulnerabilities of triple-negative breast cancer (TNBC), particularly those metabolic perturbations that increased mitochondrial apoptotic priming and sensitivity to BH3 mimetics (drugs that antagonize antiapoptotic proteins). We used high-throughput dynamic BH3 profiling (HT-DBP) to screen a library of metabolism-perturbing small molecules, which revealed inhibitors of the enzyme nicotinamide phosphoribosyltransferase (NAMPT) as top candidates. In some TNBC cells but not in nonmalignant cells, NAMPT inhibitors increased overall apoptotic priming and induced dependencies on specific antiapoptotic BCL-2 family members. Treatment of TNBC cells with NAMPT inhibitors sensitized them to subsequent treatment with BH3 mimetics. The combination of a NAMPT inhibitor (FK866) and an MCL-1 antagonist (S63845) reduced tumor growth in a TNBC patient-derived xenograft model in vivo. We found that NAMPT inhibition reduced NAD+ concentrations below a critical threshold that resulted in depletion of adenine, which was the metabolic trigger that primed TNBC cells for apoptosis. These findings demonstrate a close interaction between metabolic and mitochondrial apoptotic signaling pathways and reveal that exploitation of a tumor-specific metabolic vulnerability can sensitize some TNBC to BH3 mimetics.


Asunto(s)
Neoplasias de la Mama Triple Negativas , Apoptosis , Proteínas Reguladoras de la Apoptosis , Línea Celular Tumoral , Humanos , Mitocondrias , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Proteínas Proto-Oncogénicas c-bcl-2 , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico
5.
iScience ; 24(6): 102651, 2021 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-34151238

RESUMEN

A hallmark of acute myeloid leukemia (AML) is the inability of self-renewing malignant cells to mature into a non-dividing terminally differentiated state. This differentiation block has been linked to dysregulation of multiple cellular processes, including transcriptional, chromatin, and metabolic regulation. The transcription factor HOXA9 and the histone demethylase LSD1 are examples of such regulators that promote differentiation blockade in AML. To identify metabolic targets that interact with LSD1 inhibition to promote myeloid maturation, we screened a small molecule library to identify druggable substrates. We found that differentiation caused by LSD1 inhibition is enhanced by combined perturbation of purine nucleotide salvage and de novo lipogenesis pathways, and identified multiple lines of evidence to support the specificity of these pathways and suggest a potential basis of how perturbation of these pathways may interact synergistically to promote myeloid differentiation. In sum, these findings suggest potential drug combination strategies in the treatment of AML.

6.
Sci Adv ; 7(6)2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33547076

RESUMEN

Most intracellular proteins lack hydrophobic pockets suitable for altering their function with drug-like small molecules. Recent studies indicate that some undruggable proteins can be targeted by compounds that can degrade them. For example, thalidomide-like drugs (IMiDs) degrade the critical multiple myeloma transcription factors IKZF1 and IKZF3 by recruiting them to the cereblon E3 ubiquitin ligase. Current loss of signal ("down") assays for identifying degraders often exhibit poor signal-to-noise ratios, narrow dynamic ranges, and false positives from compounds that nonspecifically suppress transcription or translation. Here, we describe a gain of signal ("up") assay for degraders. In arrayed chemical screens, we identified novel IMiD-like IKZF1 degraders and Spautin-1, which, unlike the IMiDs, degrades IKZF1 in a cereblon-independent manner. In a pooled CRISPR-Cas9-based screen, we found that CDK2 regulates the abundance of the ASCL1 oncogenic transcription factor. This methodology should facilitate the identification of drugs that directly or indirectly degrade undruggable proteins.


Asunto(s)
Proteínas Oncogénicas , Proteolisis , Proteínas Adaptadoras Transductoras de Señales/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Bencilaminas , Sistemas CRISPR-Cas , Humanos , Factor de Transcripción Ikaros/metabolismo , Proteínas Oncogénicas/química , Proteínas Oncogénicas/metabolismo , Proteolisis/efectos de los fármacos , Quinazolinas , Talidomida/análisis , Talidomida/farmacología , Factores de Transcripción
7.
Nature ; 585(7824): 283-287, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32814897

RESUMEN

The risk of cancer and associated mortality increases substantially in humans from the age of 65 years onwards1-6. Nonetheless, our understanding of the complex relationship between age and cancer is still in its infancy2,3,7,8. For decades, this link has largely been attributed to increased exposure time to mutagens in older individuals. However, this view does not account for the established role of diet, exercise and small molecules that target the pace of metabolic ageing9-12. Here we show that metabolic alterations that occur with age can produce a systemic environment that favours the progression and aggressiveness of tumours. Specifically, we show that methylmalonic acid (MMA), a by-product of propionate metabolism, is upregulated in the serum of older people and functions as a mediator of tumour progression. We traced this to the ability of MMA to induce SOX4 expression and consequently to elicit transcriptional reprogramming that can endow cancer cells with aggressive properties. Thus, the accumulation of MMA represents a link between ageing and cancer progression, suggesting that MMA is a promising therapeutic target for advanced carcinomas.


Asunto(s)
Envejecimiento/metabolismo , Progresión de la Enfermedad , Ácido Metilmalónico/metabolismo , Invasividad Neoplásica , Metástasis de la Neoplasia , Neoplasias/patología , Adulto , Anciano , Envejecimiento/sangre , Envejecimiento/genética , Animales , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ácido Metilmalónico/sangre , Ratones , Persona de Mediana Edad , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/patología , Neoplasias/sangre , Neoplasias/genética , Factores de Transcripción SOXC/metabolismo , Transducción de Señal , Transcriptoma/genética , Factor de Crecimiento Transformador beta/metabolismo
8.
Mol Cell ; 78(6): 1096-1113.e8, 2020 06 18.
Artículo en Inglés | MEDLINE | ID: mdl-32416067

RESUMEN

BET bromodomain inhibitors (BBDIs) are candidate therapeutic agents for triple-negative breast cancer (TNBC) and other cancer types, but inherent and acquired resistance to BBDIs limits their potential clinical use. Using CRISPR and small-molecule inhibitor screens combined with comprehensive molecular profiling of BBDI response and resistance, we identified synthetic lethal interactions with BBDIs and genes that, when deleted, confer resistance. We observed synergy with regulators of cell cycle progression, YAP, AXL, and SRC signaling, and chemotherapeutic agents. We also uncovered functional similarities and differences among BRD2, BRD4, and BRD7. Although deletion of BRD2 enhances sensitivity to BBDIs, BRD7 loss leads to gain of TEAD-YAP chromatin binding and luminal features associated with BBDI resistance. Single-cell RNA-seq, ATAC-seq, and cellular barcoding analysis of BBDI responses in sensitive and resistant cell lines highlight significant heterogeneity among samples and demonstrate that BBDI resistance can be pre-existing or acquired.


Asunto(s)
Resistencia a Antineoplásicos/genética , Proteínas/antagonistas & inhibidores , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Azepinas/farmacología , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Proteínas Cromosómicas no Histona/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Ratones Endogámicos NOD , Proteínas Nucleares/metabolismo , Proteínas/metabolismo , Transducción de Señal/efectos de los fármacos , Factores de Transcripción/metabolismo , Triazoles/farmacología , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/metabolismo
9.
Cell Metab ; 29(5): 1166-1181.e6, 2019 05 07.
Artículo en Inglés | MEDLINE | ID: mdl-30799286

RESUMEN

Cells are subjected to oxidative stress during the initiation and progression of tumors, and this imposes selective pressure for cancer cells to adapt mechanisms to tolerate these conditions. Here, we examined the dependency of cancer cells on glutathione (GSH), the most abundant cellular antioxidant. While cancer cell lines displayed a broad range of sensitivities to inhibition of GSH synthesis, the majority were resistant to GSH depletion. To identify cellular pathways required for this resistance, we carried out genetic and pharmacologic screens. Both approaches revealed that inhibition of deubiquitinating enzymes (DUBs) sensitizes cancer cells to GSH depletion. Inhibition of GSH synthesis, in combination with DUB inhibition, led to an accumulation of polyubiquitinated proteins, induction of proteotoxic stress, and cell death. These results indicate that depletion of GSH renders cancer cells dependent on DUB activity to maintain protein homeostasis and cell viability and reveal a potentially exploitable vulnerability for cancer therapy.


Asunto(s)
Antioxidantes/metabolismo , Supervivencia Celular/efectos de los fármacos , Enzimas Desubicuitinizantes/metabolismo , Glutatión/metabolismo , Proteostasis/efectos de los fármacos , Células A549 , Aminopiridinas/farmacología , Animales , Butionina Sulfoximina/farmacología , Dominio Catalítico/efectos de los fármacos , Enzimas Desubicuitinizantes/antagonistas & inhibidores , Femenino , Glutamato-Cisteína Ligasa/antagonistas & inhibidores , Glutamato-Cisteína Ligasa/química , Glutamato-Cisteína Ligasa/metabolismo , Humanos , Células MCF-7 , Glándulas Mamarias Animales/citología , Glándulas Mamarias Humanas/citología , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Organoides/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Tiocianatos/farmacología , Carga Tumoral/efectos de los fármacos , Proteínas Ubiquitinadas/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
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