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1.
Genes Dev ; 31(13): 1339-1353, 2017 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-28790158

RESUMEN

Lung adenocarcinoma accounts for ∼40% of lung cancers, the leading cause of cancer-related death worldwide, and current therapies provide only limited survival benefit. Approximately half of lung adenocarcinomas harbor mutations in TP53 (p53), making these mutants appealing targets for lung cancer therapy. As mutant p53 remains untargetable, mutant p53-dependent phenotypes represent alternative targeting opportunities, but the prevalence and therapeutic relevance of such effects (gain of function and dominant-negative activity) in lung adenocarcinoma are unclear. Through transcriptional and functional analysis of murine KrasG12D -p53null , -p53R172H (conformational), and -p53R270H (contact) mutant lung tumors, we identified genotype-independent and genotype-dependent therapeutic sensitivities. Unexpectedly, we found that wild-type p53 exerts a dominant tumor-suppressive effect on mutant tumors, as all genotypes were similarly sensitive to its restoration in vivo. These data show that the potential of p53 targeted therapies is comparable across all p53-deficient genotypes and may explain the high incidence of p53 loss of heterozygosity in mutant tumors. In contrast, mutant p53 gain of function and their associated vulnerabilities can vary according to mutation type. Notably, we identified a p53R270H -specific sensitivity to simvastatin in lung tumors, and the transcriptional signature that underlies this sensitivity was also present in human lung tumors, indicating that this therapeutic approach may be clinically relevant.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Simvastatina/uso terapéutico , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Adenocarcinoma del Pulmón , Animales , Antineoplásicos/farmacología , Puntos de Control del Ciclo Celular/genética , Muerte Celular/genética , Línea Celular Tumoral , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Genotipo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Imidazoles/farmacología , Ratones , Terapia Molecular Dirigida , Mutación , Piperazinas/farmacología , Simvastatina/farmacología
2.
Nature ; 531(7592): 110-3, 2016 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-26909577

RESUMEN

The RAS/MAPK (mitogen-activated protein kinase) signalling pathway is frequently deregulated in non-small-cell lung cancer, often through KRAS activating mutations. A single endogenous mutant Kras allele is sufficient to promote lung tumour formation in mice but malignant progression requires additional genetic alterations. We recently showed that advanced lung tumours from Kras(G12D/+);p53-null mice frequently exhibit Kras(G12D) allelic enrichment (Kras(G12D)/Kras(wild-type) > 1) (ref. 7), implying that mutant Kras copy gains are positively selected during progression. Here we show, through a comprehensive analysis of mutant Kras homozygous and heterozygous mouse embryonic fibroblasts and lung cancer cells, that these genotypes are phenotypically distinct. In particular, Kras(G12D/G12D) cells exhibit a glycolytic switch coupled to increased channelling of glucose-derived metabolites into the tricarboxylic acid cycle and glutathione biosynthesis, resulting in enhanced glutathione-mediated detoxification. This metabolic rewiring is recapitulated in mutant KRAS homozygous non-small-cell lung cancer cells and in vivo, in spontaneous advanced murine lung tumours (which display a high frequency of Kras(G12D) copy gain), but not in the corresponding early tumours (Kras(G12D) heterozygous). Finally, we demonstrate that mutant Kras copy gain creates unique metabolic dependences that can be exploited to selectively target these aggressive mutant Kras tumours. Our data demonstrate that mutant Kras lung tumours are not a single disease but rather a heterogeneous group comprising two classes of tumours with distinct metabolic profiles, prognosis and therapeutic susceptibility, which can be discriminated on the basis of their relative mutant allelic content. We also provide the first, to our knowledge, in vivo evidence of metabolic rewiring during lung cancer malignant progression.


Asunto(s)
Variaciones en el Número de Copia de ADN/genética , Genes ras/genética , Glucosa/metabolismo , Glucólisis , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Mutación/genética , Alelos , Animales , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Ciclo del Ácido Cítrico , Progresión de la Enfermedad , Femenino , Fibroblastos/metabolismo , Genotipo , Glutatión/biosíntesis , Glutatión/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Ratones , Oxidación-Reducción , Fenotipo , Pronóstico
3.
Genes Dev ; 25(16): 1746-57, 2011 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-21852537

RESUMEN

MdmX, also known as Mdm4, is a critical negative regulator of p53, and its overexpression serves to block p53 tumor suppressor function in many cancers. Consequently, inhibiting MdmX has emerged as an attractive approach to restoring p53 function in those cancers that retain functional p53. However, the consequences of acute systemic MdmX inhibition in normal adult tissues remain unknown. To determine directly the effects of systemic MdmX inhibition in normal tissues and in tumors, we crossed mdmX(-/-) mice into the p53ER(TAM) knockin background. In place of wild-type p53, p53ER(TAM) knockin mice express a variant of p53, p53ER(TAM), that is completely dependent on 4-hydroxy-tamoxifen for its activity. MdmX inhibition was then modeled by restoring p53 function in these MdmX-deficient mice. We show that MdmX is continuously required to buffer p53 activity in adult normal tissues and their stem cells. Importantly, the effects of transient p53 restoration in the absence of MdmX are nonlethal and reversible, unlike transient p53 restoration in the absence of Mdm2, which is ineluctably lethal. We also show that the therapeutic impact of restoring p53 in a tumor model is enhanced in the absence of MdmX, affording a significant extension of life span over p53 restoration in the presence of MdmX. Hence, systemic inhibition of MdmX is both a feasible therapeutic strategy for restoring p53 function in tumors that retain wild-type p53 and likely to be significantly safer than inhibition of Mdm2.


Asunto(s)
Linfoma/genética , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteínas Proto-Oncogénicas/genética , Proteína p53 Supresora de Tumor/genética , Ubiquitina-Proteína Ligasas/genética , Animales , Antineoplásicos Hormonales/farmacología , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Médula Ósea/efectos de los fármacos , Médula Ósea/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Embrión de Mamíferos/citología , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Expresión Génica/efectos de los fármacos , Immunoblotting , Estimación de Kaplan-Meier , Hígado/efectos de los fármacos , Hígado/metabolismo , Linfoma/tratamiento farmacológico , Linfoma/patología , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Mutación , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Tamoxifeno/análogos & derivados , Tamoxifeno/farmacología , Células Tumorales Cultivadas , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo
4.
Nature ; 468(7323): 567-71, 2010 Nov 25.
Artículo en Inglés | MEDLINE | ID: mdl-21107427

RESUMEN

Non-small cell lung carcinoma (NSCLC) is the leading cause of cancer-related death worldwide, with an overall 5-year survival rate of only 10-15%. Deregulation of the Ras pathway is a frequent hallmark of NSCLC, often through mutations that directly activate Kras. p53 is also frequently inactivated in NSCLC and, because oncogenic Ras can be a potent trigger of p53 (ref. 3), it seems likely that oncogenic Ras signalling has a major and persistent role in driving the selection against p53. Hence, pharmacological restoration of p53 is an appealing therapeutic strategy for treating this disease. Here we model the probable therapeutic impact of p53 restoration in a spontaneously evolving mouse model of NSCLC initiated by sporadic oncogenic activation of endogenous Kras. Surprisingly, p53 restoration failed to induce significant regression of established tumours, although it did result in a significant decrease in the relative proportion of high-grade tumours. This is due to selective activation of p53 only in the more aggressive tumour cells within each tumour. Such selective activation of p53 correlates with marked upregulation in Ras signal intensity and induction of the oncogenic signalling sensor p19(ARF)( )(ref. 6). Our data indicate that p53-mediated tumour suppression is triggered only when oncogenic Ras signal flux exceeds a critical threshold. Importantly, the failure of low-level oncogenic Kras to engage p53 reveals inherent limits in the capacity of p53 to restrain early tumour evolution and in the efficacy of therapeutic p53 restoration to eradicate cancers.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/fisiopatología , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/fisiopatología , Proteína p53 Supresora de Tumor/metabolismo , Animales , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Proliferación Celular , Modelos Animales de Enfermedad , Neoplasias Pulmonares/metabolismo , Ratones , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteínas ras/metabolismo
5.
Nature ; 455(7213): 679-83, 2008 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-18716624

RESUMEN

Myc is a pleiotropic basic helix-loop-helix leucine zipper transcription factor that coordinates expression of the diverse intracellular and extracellular programs that together are necessary for growth and expansion of somatic cells. In principle, this makes inhibition of Myc an attractive pharmacological approach for treating diverse types of cancer. However, enthusiasm has been muted by lack of direct evidence that Myc inhibition would be therapeutically efficacious, concerns that it would induce serious side effects by inhibiting proliferation of normal tissues, and practical difficulties in designing Myc inhibitory drugs. We have modelled genetically both the therapeutic impact and the side effects of systemic Myc inhibition in a preclinical mouse model of Ras-induced lung adenocarcinoma by reversible, systemic expression of a dominant-interfering Myc mutant. We show that Myc inhibition triggers rapid regression of incipient and established lung tumours, defining an unexpected role for endogenous Myc function in the maintenance of Ras-dependent tumours in vivo. Systemic Myc inhibition also exerts profound effects on normal regenerating tissues. However, these effects are well tolerated over extended periods and rapidly and completely reversible. Our data demonstrate the feasibility of targeting Myc, a common downstream conduit for many oncogenic signals, as an effective, efficient and tumour-specific cancer therapy.


Asunto(s)
Terapia Genética , Neoplasias Pulmonares/terapia , Modelos Biológicos , Proteínas Proto-Oncogénicas c-myc/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-myc/genética , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adenocarcinoma/terapia , Animales , Tracto Gastrointestinal/citología , Tracto Gastrointestinal/metabolismo , Tracto Gastrointestinal/patología , Genes Dominantes/genética , Genes ras , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Ratones , Mutación/genética , Proteína Oncogénica p21(ras)/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Piel/citología , Piel/metabolismo , Piel/patología , Testículo/citología , Testículo/metabolismo , Testículo/patología , Transgenes/genética
6.
Nat Commun ; 15(1): 1700, 2024 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-38402224

RESUMEN

The Ataxia telangiectasia and Rad3-related (ATR) inhibitor ceralasertib in combination with the PD-L1 antibody durvalumab demonstrated encouraging clinical benefit in melanoma and lung cancer patients who progressed on immunotherapy. Here we show that modelling of intermittent ceralasertib treatment in mouse tumor models reveals CD8+ T-cell dependent antitumor activity, which is separate from the effects on tumor cells. Ceralasertib suppresses proliferating CD8+ T-cells on treatment which is rapidly reversed off-treatment. Ceralasertib causes up-regulation of type I interferon (IFNI) pathway in cancer patients and in tumor-bearing mice. IFNI is experimentally found to be a major mediator of antitumor activity of ceralasertib in combination with PD-L1 antibody. Improvement of T-cell function after ceralasertib treatment is linked to changes in myeloid cells in the tumor microenvironment. IFNI also promotes anti-proliferative effects of ceralasertib on tumor cells. Here, we report that broad immunomodulatory changes following intermittent ATR inhibition underpins the clinical therapeutic benefit and indicates its wider impact on antitumor immunity.


Asunto(s)
Linfocitos T CD8-positivos , Indoles , Morfolinas , Neoplasias , Pirimidinas , Sulfonamidas , Humanos , Animales , Ratones , Antígeno B7-H1 , Microambiente Tumoral , Línea Celular Tumoral , Inmunoterapia , Modelos Animales de Enfermedad , Proteínas de la Ataxia Telangiectasia Mutada
7.
Drug Resist Updat ; 15(5-6): 258-67, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23164556

RESUMEN

The p53 transcription factor was first described over three decades ago and is one of the most studied proteins, with over 60,000 PubMed listed publications. Despite being first described as an oncogene, p53 has long been recognized as a major tumor suppressor and the most commonly mutated gene in human cancer. The frequent inactivation of p53 in tumors fostered the attractive notion that its functional reinstatement would constitute an effective tumor-specific therapy. Strategies aimed at restoring wild-type p53 function in tumors are being actively pursued and some have reached clinical trials, highlighting the important translational potential of this new field of research. The therapeutic impact of those strategies in human cancer was recently modeled in mice where a clear, even if limited, therapeutic benefit of p53-targeted therapies was established. As unexpected aspects of p53 tumor suppressive function continue to be uncovered, new opportunities arise to further improve p53 therapy outcome. In this review we discuss the in vivo mechanisms underlying p53-mediated tumor prevention, the impact of p53 functional restoration in tumors and how this knowledge may be exploited to improve the efficacy of p53-targeted cancer therapy. A particular emphasis is given to the newly identified metabolic functions of p53.


Asunto(s)
Neoplasias/tratamiento farmacológico , Proteína p53 Supresora de Tumor/metabolismo , Animales , Humanos , Ratones , Mutación , Neoplasias/genética , Neoplasias/prevención & control , Proteína p53 Supresora de Tumor/genética
8.
Mol Cancer Ther ; 21(10): 1535-1546, 2022 10 07.
Artículo en Inglés | MEDLINE | ID: mdl-35930755

RESUMEN

AZD4625 is a potent, selective, and orally bioavailable inhibitor of oncogenic KRASG12C as demonstrated in cellular assays and in vivo in preclinical cell line-derived and patient-derived xenograft models. In vitro and cellular assays have shown selective binding and inhibition of the KRASG12C mutant isoform, which carries a glycine to cysteine mutation at residue 12, with no binding and inhibition of wild-type RAS or isoforms carrying non-KRASG12C mutations. The pharmacology of AZD4625 shows that it has the potential to provide therapeutic benefit to patients with KRASG12C mutant cancer as either a monotherapy treatment or in combination with other targeted drug agents.


Asunto(s)
Antineoplásicos , Cisteína , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Glicina/farmacología , Humanos , Mutación , Isoformas de Proteínas , Ensayos Antitumor por Modelo de Xenoinjerto
9.
Nat Commun ; 12(1): 683, 2021 01 29.
Artículo en Inglés | MEDLINE | ID: mdl-33514748

RESUMEN

Tumors consist of cancer cells and a network of non-cancerous stroma. Cancer-associated fibroblasts (CAF) are known to support tumorigenesis, and are emerging as immune modulators. Neutrophils release histone-bound nuclear DNA and cytotoxic granules as extracellular traps (NET). Here we show that CAFs induce NET formation within the tumor and systemically in the blood and bone marrow. These tumor-induced NETs (t-NETs) are driven by a ROS-mediated pathway dependent on CAF-derived Amyloid ß, a peptide implicated in both neurodegenerative and inflammatory disorders. Inhibition of NETosis in murine tumors skews neutrophils to an anti-tumor phenotype, preventing tumor growth; reciprocally, t-NETs enhance CAF activation. Mirroring observations in mice, CAFs are detected juxtaposed to NETs in human melanoma and pancreatic adenocarcinoma, and show elevated amyloid and ß-Secretase expression which correlates with poor prognosis. In summary, we report that CAFs drive NETosis to support cancer progression, identifying Amyloid ß as the protagonist and potential therapeutic target.


Asunto(s)
Péptidos beta-Amiloides/metabolismo , Fibroblastos Asociados al Cáncer/metabolismo , Trampas Extracelulares/metabolismo , Neoplasias/patología , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Médula Ósea/patología , Antígeno CD11b/metabolismo , Fibroblastos Asociados al Cáncer/efectos de los fármacos , Carcinogénesis/patología , Comunicación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Trampas Extracelulares/efectos de los fármacos , Femenino , Voluntarios Sanos , Humanos , Masculino , Ratones , Ratones Transgénicos , Neoplasias/sangre , Neoplasias/genética , Neoplasias/mortalidad , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Estudios Observacionales como Asunto , Cultivo Primario de Células , Pronóstico , Arginina Deiminasa Proteína-Tipo 4/antagonistas & inhibidores , Arginina Deiminasa Proteína-Tipo 4/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Células Tumorales Cultivadas , Microambiente Tumoral/efectos de los fármacos
10.
Nat Commun ; 11(1): 4903, 2020 09 29.
Artículo en Inglés | MEDLINE | ID: mdl-32994412

RESUMEN

The CRISPR-Cas9 system has increased the speed and precision of genetic editing in cells and animals. However, model generation for drug development is still expensive and time-consuming, demanding more target flexibility and faster turnaround times with high reproducibility. The generation of a tightly controlled ObLiGaRe doxycycline inducible SpCas9 (ODInCas9) transgene and its use in targeted ObLiGaRe results in functional integration into both human and mouse cells culminating in the generation of the ODInCas9 mouse. Genomic editing can be performed in cells of various tissue origins without any detectable gene editing in the absence of doxycycline. Somatic in vivo editing can model non-small cell lung cancer (NSCLC) adenocarcinomas, enabling treatment studies to validate the efficacy of candidate drugs. The ODInCas9 mouse allows robust and tunable genome editing granting flexibility, speed and uniformity at less cost, leading to high throughput and practical preclinical in vivo therapeutic testing.


Asunto(s)
Sistemas CRISPR-Cas/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Descubrimiento de Drogas/métodos , Edición Génica/métodos , Neoplasias Pulmonares/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Proteína 9 Asociada a CRISPR/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Línea Celular Tumoral , Doxiciclina/farmacología , Ensayos de Selección de Medicamentos Antitumorales/métodos , Femenino , Expresión Génica/efectos de los fármacos , Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Vectores Genéticos/genética , Células HEK293 , Ensayos Analíticos de Alto Rendimiento/métodos , Humanos , Neoplasias Pulmonares/genética , Masculino , Ratones , Ratones Transgénicos , ARN Guía de Kinetoplastida/genética , Recombinación Genética/efectos de los fármacos , Reproducibilidad de los Resultados , Activación Transcripcional/efectos de los fármacos , Transfección/métodos , Transgenes/genética
11.
Aging Cell ; 19(4): e13142, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32233024

RESUMEN

Pharmacologically active compounds with preferential cytotoxic activity for senescent cells, known as senolytics, can ameliorate or even revert pathological manifestations of senescence in numerous preclinical mouse disease models, including cancer models. However, translation of senolytic therapies to human disease is hampered by their suboptimal specificity for senescent cells and important toxicities that narrow their therapeutic windows. We have previously shown that the high levels of senescence-associated lysosomal ß-galactosidase (SA-ß-gal) found within senescent cells can be exploited to specifically release tracers and cytotoxic cargoes from galactose-encapsulated nanoparticles within these cells. Here, we show that galacto-conjugation of the BCL-2 family inhibitor Navitoclax results in a potent senolytic prodrug (Nav-Gal), that can be preferentially activated by SA-ß-gal activity in a wide range of cell types. Nav-Gal selectively induces senescent cell apoptosis and has a higher senolytic index than Navitoclax (through reduced activation in nonsenescent cells). Nav-Gal enhances the cytotoxicity of standard senescence-inducing chemotherapy (cisplatin) in human A549 lung cancer cells. Concomitant treatment with cisplatin and Nav-Gal in vivo results in the eradication of senescent lung cancer cells and significantly reduces tumour growth. Importantly, galacto-conjugation reduces Navitoclax-induced platelet apoptosis in human and murine blood samples treated ex vivo, and thrombocytopenia at therapeutically effective concentrations in murine lung cancer models. Taken together, we provide a potentially versatile strategy for generating effective senolytic prodrugs with reduced toxicities.


Asunto(s)
Compuestos de Anilina/farmacología , Antineoplásicos/farmacología , Plaquetas/efectos de los fármacos , Galactosa/farmacología , Profármacos/farmacología , Sulfonamidas/farmacología , Compuestos de Anilina/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Galactosa/química , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones SCID , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Profármacos/síntesis química , Profármacos/química , Sulfonamidas/química , Células Tumorales Cultivadas
12.
FEBS J ; 285(1): 28-41, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-28570035

RESUMEN

Lung cancer is the leading cause of cancer-related death worldwide, reflecting an unfortunate combination of very high prevalence and low survival rates, as most cases are diagnosed at advanced stages when treatment efficacy is limited. Lung cancer comprises several disease groups with non small cell lung cancer (NSCLC) accounting for ~ 85% of cases and lung adenocarcinoma being its most frequent histological subtype. Mutations in Kirsten rat sarcoma viral oncogene homologue (KRAS) affect ~ 30% of lung adenocarcinomas but unlike other commonly altered proteins (EGFR and ALK, affected in ~ 14% and 7% of cases respectively), mutant KRAS remains untargetable. Therapeutic strategies that rely instead on the inhibition of mutant KRAS functional output or the targeting of mutant KRAS cellular dependencies (i.e. synthetic lethality) are an appealing alternative approach. Recent studies focused on the metabolic properties of mutant KRAS lung tumours have uncovered unique metabolic features that can potentially be exploited therapeutically. We review these findings here with a particular focus on in vivo, physiologic, mutant KRAS activity.


Asunto(s)
Adenocarcinoma/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Mutación , Proteínas Proto-Oncogénicas p21(ras)/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/terapia , Animales , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/terapia , Glucosa/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , Proteínas Proto-Oncogénicas p21(ras)/metabolismo
13.
Nat Commun ; 9(1): 948, 2018 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-29507342

RESUMEN

Tumours have developed strategies to interfere with most steps required for anti-tumour immune responses. Although many populations contribute to anti-tumour responses, tumour-infiltrating cytotoxic T cells dominate, hence, many suppressive strategies act to inhibit these. Tumour-associated T cells are frequently restricted to stromal zones rather than tumour islands, raising the possibility that the tumour microenvironment, where crosstalk between malignant and "normal" stromal cells exists, may be critical for T cell suppression. We provide evidence of direct interactions between stroma and T cells driving suppression, showing that cancer-associated fibroblasts (CAFs) sample, process and cross-present antigen, killing CD8+ T cells in an antigen-specific, antigen-dependent manner via PD-L2 and FASL. Inhibitory ligand expression is observed in CAFs from human tumours, and neutralisation of PD-L2 or FASL reactivates T cell cytotoxic capacity in vitro and in vivo. Thus, CAFs support T cell suppression within the tumour microenvironment by a mechanism dependent on immune checkpoint activation.


Asunto(s)
Antígenos de Neoplasias/inmunología , Linfocitos T CD8-positivos/inmunología , Fibroblastos Asociados al Cáncer/patología , Citoprotección , Animales , Supervivencia Celular , Reactividad Cruzada/inmunología , Citotoxicidad Inmunológica , Proteína Ligando Fas/metabolismo , Femenino , Ratones Endogámicos C57BL , Proteína 2 Ligando de Muerte Celular Programada 1/metabolismo , Proteolisis
14.
Nat Commun ; 9(1): 3011, 2018 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-30069015

RESUMEN

Osmotic regulation is a vital homoeostatic process in all cells and tissues. Cells initially respond to osmotic stresses by activating transmembrane transport proteins to move osmotically active ions. Disruption of ion and water transport is frequently observed in cellular transformations such as cancer. We report that genes involved in membrane transport are significantly deregulated in many cancers, and that their expression can distinguish cancer cells from normal cells with a high degree of accuracy. We present an executable model of osmotic regulation and membrane transport in mammalian cells, providing a mechanistic explanation for phenotype change in varied disease states, and accurately predicting behaviour from single cell expression data. We also predict key proteins involved in cellular transformation, SLC4A3 (AE3), and SLC9A1 (NHE1). Furthermore, we predict and verify a synergistic drug combination in vitro, of sodium and chloride channel inhibitors, which target the osmoregulatory network to reduce cancer-associated phenotypes in fibroblasts.


Asunto(s)
Modelos Biológicos , Neoplasias/metabolismo , Osmorregulación , Animales , Transporte Biológico , Embrión de Mamíferos/citología , Fibroblastos/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones Endogámicos C57BL , Neoplasias/genética , Fenotipo , Células del Estroma/metabolismo
15.
Sci Transl Med ; 10(446)2018 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-29925636

RESUMEN

KRAS is the most frequently mutated driver oncogene in human adenocarcinoma of the lung. There are presently no clinically proven strategies for treatment of KRAS-driven lung cancer. Activating mutations in KRAS are thought to confer independence from upstream signaling; however, recent data suggest that this independence may not be absolute. We show that initiation and progression of KRAS-driven lung tumors require input from ERBB family receptor tyrosine kinases (RTKs): Multiple ERBB RTKs are expressed and active from the earliest stages of KRAS-driven lung tumor development, and treatment with a multi-ERBB inhibitor suppresses formation of KRASG12D-driven lung tumors. We present evidence that ERBB activity amplifies signaling through the core RAS pathway, supporting proliferation of KRAS-mutant tumor cells in culture and progression to invasive disease in vivo. Brief pharmacological inhibition of the ERBB network enhances the therapeutic benefit of MEK (mitogen-activated protein kinase kinase) inhibition in an autochthonous tumor setting. Our data suggest that lung cancer patients with KRAS-driven disease may benefit from inclusion of multi-ERBB inhibitors in rationally designed treatment strategies.


Asunto(s)
Carcinogénesis/metabolismo , Carcinogénesis/patología , Receptores ErbB/metabolismo , Redes Reguladoras de Genes , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Animales , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Progresión de la Enfermedad , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Mutación/genética , Fosforilación , Transducción de Señal , Análisis de Supervivencia
16.
Trends Mol Med ; 23(5): 377-378, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-28372922

RESUMEN

The identification of therapeutic vulnerabilities in mutant KRAS tumors has proven difficult to achieve. Burgess and colleagues recently reported in Cell that mutant/wild-type Kras allelic dosage determines clonal fitness and MEK inhibitor sensitivity in a leukemia model, demonstrating that KRAS allelic imbalance is likely an important and overlooked variable.


Asunto(s)
Desequilibrio Alélico/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Benzamidas/farmacología , Difenilamina/análogos & derivados , Difenilamina/farmacología , Dosificación de Gen/genética , Humanos , Leucemia/genética , MAP Quinasa Quinasa 1/antagonistas & inhibidores , MAP Quinasa Quinasa 1/metabolismo , MAP Quinasa Quinasa 2/antagonistas & inhibidores , MAP Quinasa Quinasa 2/metabolismo , Modelos Teóricos
17.
J Nucl Med ; 55(7): 1144-9, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24777291

RESUMEN

UNLABELLED: Tumors are often characterized by high levels of de novo fatty acid synthesis. The kinetics of acetate incorporation into tricarboxylic acid cycle intermediates and into lipids suggest that detection of tumors with [1-(11)C]acetate PET could be improved by imaging at later time points. METHODS: The uptake and metabolism of [1-(11)C], [1-(13)C], and [1-(14)C]acetate were measured in mouse prostate and lung cancer models to investigate the time course of (11)C label incorporation into tumor metabolites. RESULTS: Radioactivity in the lipid fraction, as compared with the aqueous fraction, in extracts of C4-2B human prostate xenografts peaked at 90 min after [1-(14)C]acetate injection, which coincided with peak (13)C label incorporation into the fatty acids palmitate and stearate. Contrast between the tumor and tissues, such as blood and muscle, increased in PET images acquired over a period of 120 min after [1-(11)C]acetate injection, and Patlak plots were linear from 17.5 min after injection. Similar results were obtained in a genetically engineered K-ras(G12D); p53(null) lung cancer model, in which the mean tumor-to-lung ratio at 90 min after [1-(14)C]acetate injection was 4.4-fold higher than at 15 min. CONCLUSION: These findings suggest that when imaging de novo fatty acid synthesis with [1-(11)C]acetate it is preferable to measure uptake at later time points, when the effects of perfusion and (11)C incorporation into tricarboxylic acid cycle intermediates and bicarbonate are declining. The data presented here suggest that future clinical PET scans of tumors should be acquired later than 30 min, when tracer accumulation due to de novo fatty acid synthesis prevails.


Asunto(s)
Acetatos , Ácidos Grasos/biosíntesis , Neoplasias Pulmonares/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Neoplasias de la Próstata/diagnóstico por imagen , Animales , Radioisótopos de Carbono , Neoplasias Pulmonares/metabolismo , Masculino , Ratones , Neoplasias de la Próstata/metabolismo , Factores de Tiempo , Tomografía Computarizada por Rayos X
18.
PLoS One ; 8(9): e73817, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24040083

RESUMEN

SALL2- a member of the Spalt gene family- is a poorly characterized transcription factor found deregulated in various cancers, which suggests it plays a role in the disease. We previously identified SALL2 as a novel interacting protein of neurotrophin receptors and showed that it plays a role in neuronal function, which does not necessarily explain why or how SALL2 is deregulated in cancer. Previous evidences indicate that SALL2 gene is regulated by the WT1 and AP4 transcription factors. Here, we identified SALL2 as a novel downstream target of the p53 tumor suppressor protein. Bioinformatic analysis of the SALL2 gene revealed several putative p53 half sites along the promoter region. Either overexpression of wild-type p53 or induction of the endogenous p53 by the genotoxic agent doxorubicin repressed SALL2 promoter activity in various cell lines. However R175H, R249S, and R248W p53 mutants, frequently found in the tumors of cancer patients, were unable to repress SALL2 promoter activity, suggesting that p53 specific binding to DNA is important for the regulation of SALL2. Electrophoretic mobility shift assay demonstrated binding of p53 to one of the identified p53 half sites in the Sall2 promoter, and chromatin immunoprecipitation analysis confirmed in vivo interaction of p53 with the promoter region of Sall2 containing this half site. Importantly, by using a p53ER (TAM) knockin model expressing a variant of p53 that is completely dependent on 4-hydroxy-tamoxifen for its activity, we show that p53 activation diminished SALL2 RNA and protein levels during genotoxic cellular stress in primary mouse embryo fibroblasts (MEFs) and radiosensitive tissues in vivo. Thus, our finding indicates that p53 represses SALL2 expression in a context-specific manner, adding knowledge to the understanding of SALL2 gene regulation, and to a potential mechanism for its deregulation in cancer.


Asunto(s)
Daño del ADN , Regulación de la Expresión Génica/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Proteína p53 Supresora de Tumor/genética , Animales , Antibióticos Antineoplásicos/farmacología , Secuencia de Bases , Sitios de Unión/genética , Western Blotting , Línea Celular Tumoral , Células Cultivadas , Proteínas de Unión al ADN , Doxorrubicina/farmacología , Embrión de Mamíferos/citología , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Células HCT116 , Células HEK293 , Humanos , Ratones , Ratones Transgénicos , Datos de Secuencia Molecular , Mutación , Regiones Promotoras Genéticas/genética , Unión Proteica , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Homología de Secuencia de Ácido Nucleico , Factores de Transcripción , Proteína p53 Supresora de Tumor/metabolismo
19.
Cancer Res ; 70(2): 520-31, 2010 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-20068150

RESUMEN

The cyclin dependent kinase (CDK) inhibitors p15, p16, p21, and p27 are frequently deleted, silenced, or downregulated in many malignancies. Inactivation of CDK inhibitors predisposes mice to tumor development, showing that these genes function as tumor suppressors. Here, we describe high-throughput murine leukemia virus insertional mutagenesis screens in mice that are deficient for one or two CDK inhibitors. We retrieved 9,117 retroviral insertions from 476 lymphomas to define hundreds of loci that are mutated more frequently than expected by chance. Many of these loci are skewed toward a specific genetic context of predisposing germline and somatic mutations. We also found associations between these loci with gender, age of tumor onset, and lymphocyte lineage (B or T cell). Comparison of retroviral insertion sites with single nucleotide polymorphisms associated with chronic lymphocytic leukemia revealed a significant overlap between the datasets. Together, our findings highlight the importance of genetic context within large-scale mutation detection studies, and they show a novel use for insertional mutagenesis data in prioritizing disease-associated genes that emerge from genome-wide association studies.


Asunto(s)
Proteínas Inhibidoras de las Quinasas Dependientes de la Ciclina/genética , Mutagénesis Insercional/genética , Neoplasias Experimentales/genética , Animales , Proteínas Inhibidoras de las Quinasas Dependientes de la Ciclina/deficiencia , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/deficiencia , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/deficiencia , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/deficiencia , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/deficiencia , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Femenino , Virus de la Leucemia Murina/genética , Leucemia Linfocítica Crónica de Células B/genética , Linfoma/genética , Masculino , Ratones , Células 3T3 NIH , Polimorfismo de Nucleótido Simple
20.
Cell ; 127(7): 1323-34, 2006 Dec 29.
Artículo en Inglés | MEDLINE | ID: mdl-17182091

RESUMEN

Although restoration of p53 function is an attractive tumor-specific therapeutic strategy, it remains unclear whether p53 loss is required only for transition through early bottlenecks in tumorigenesis or also for maintenance of established tumors. To explore the efficacy of p53 reinstatement as a tumor therapy, we used a reversibly switchable p53 knockin (KI) mouse model that permits modulation of p53 status from wild-type to knockout, at will. Using the well-characterized Emu-myc lymphoma model, we show that p53 is spontaneously activated when restored in established Emu-myc lymphomas in vivo, triggering rapid apoptosis and conferring a significant increase in survival. Nonetheless, reimposition of p53 function potently selects for emergence of p53-resistant tumors through inactivation of p19(ARF) or p53. Our study provides important insights into the nature and timing of p53-activating signals in established tumors and how resistance to p53 evolves, which will aid in the optimization of p53-based tumor therapies.


Asunto(s)
Linfoma/terapia , Proteínas Proto-Oncogénicas c-myc/genética , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Alelos , Animales , Daño del ADN , Dosificación de Gen , Linfoma/inducido químicamente , Linfoma/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Trasplante de Neoplasias , Transducción de Señal
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