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1.
Cancer Discov ; 14(5): 846-865, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38456804

RESUMEN

Oncology drug combinations can improve therapeutic responses and increase treatment options for patients. The number of possible combinations is vast and responses can be context-specific. Systematic screens can identify clinically relevant, actionable combinations in defined patient subtypes. We present data for 109 anticancer drug combinations from AstraZeneca's oncology small molecule portfolio screened in 755 pan-cancer cell lines. Combinations were screened in a 7 × 7 concentration matrix, with more than 4 million measurements of sensitivity, producing an exceptionally data-rich resource. We implement a new approach using combination Emax (viability effect) and highest single agent (HSA) to assess combination benefit. We designed a clinical translatability workflow to identify combinations with clearly defined patient populations, rationale for tolerability based on tumor type and combination-specific "emergent" biomarkers, and exposures relevant to clinical doses. We describe three actionable combinations in defined cancer types, confirmed in vitro and in vivo, with a focus on hematologic cancers and apoptotic targets. SIGNIFICANCE: We present the largest cancer drug combination screen published to date with 7 × 7 concentration response matrices for 109 combinations in more than 750 cell lines, complemented by multi-omics predictors of response and identification of "emergent" combination biomarkers. We prioritize hits to optimize clinical translatability, and experimentally validate novel combination hypotheses. This article is featured in Selected Articles from This Issue, p. 695.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias , Humanos , Línea Celular Tumoral , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ensayos de Selección de Medicamentos Antitumorales/métodos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico
3.
NPJ Breast Cancer ; 9(1): 64, 2023 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-37543694

RESUMEN

Combining the selective AKT inhibitor, capivasertib, and SERD, fulvestrant improved PFS in a Phase III clinical trial (CAPItello-291), treating HR+ breast cancer patients following aromatase inhibitors, with or without CDK4/6 inhibitors. However, clinical data suggests CDK4/6 treatment may reduce response to subsequent monotherapy endocrine treatment. To support understanding of trials such as CAPItello-291 and gain insight into this emerging population of patients, we explored how CDK4/6 inhibitor treatment influences ER+ breast tumour cell function and response to fulvestrant and capivasertib after CDK4/6 inhibitor treatment. In RB+, RB- T47D and MCF7 palbociclib-resistant cells ER pathway ER and Greb-1 expression were reduced versus naïve cells. PI3K-AKT pathway activation was also modified in RB+ cells, with capivasertib less effective at reducing pS6 in RB+ cells compared to parental cells. Expression profiling of parental versus palbociclib-resistant cells confirmed capivasertib, fulvestrant and the combination differentially impacted gene expression modulation in resistant cells, with different responses seen in T47D and MCF7 cells. Fulvestrant inhibition of ER-dependent genes was reduced. In resistant cells, the combination was less effective at reducing cell cycle genes, but a consistent reduction in cell fraction in S-phase was observed in naïve and resistant cells. Despite modified signalling responses, both RB+ and RB- resistant cells responded to combination treatment despite some reduction in relative efficacy and was effective in vivo in palbociclib-resistant PDX models. Collectively these findings demonstrate that simultaneous inhibition of AKT and ER signalling can be effective in models representing palbociclib resistance despite changes in pathway dependency.

5.
Oncogene ; 37(28): 3763-3777, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29636547

RESUMEN

Previous reports have demonstrated that select cancers depend on BRD4 to regulate oncogenic gene transcriptional programs. Here we describe a novel role for BRD4 in DNA damage response (DDR). BRD4 associates with and regulates the function of pre-replication factor CDC6 and plays an indispensable part in DNA replication checkpoint signaling. Inhibition of BRD4 by JQ1 or AZD5153 resulted in a rapid, time-dependent reduction in CHK1 phosphorylation and aberrant DNA replication re-initiation. Furthermore, BRD4 inhibition sensitized cancer cells to various replication stress-inducing agents, and synergized with ATR inhibitor AZD6738 to induce cell killing across a number of cancer cell lines. The synergistic interaction between AZD5153 and AZD6738 is translatable to in vivo ovarian cell-line and patient-derived xenograft models. Taken together, our study uncovers a new biological function of BRD4 and provides mechanistic rationale for combining BET inhibitors with DDR-targeted agents for cancer therapy.


Asunto(s)
Daño del ADN/genética , Replicación del ADN/genética , Proteínas Nucleares/genética , Factores de Transcripción/genética , Animales , Proteínas de Ciclo Celular , Línea Celular Tumoral , Daño del ADN/efectos de los fármacos , Replicación del ADN/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/genética , Compuestos Heterocíclicos con 2 Anillos/farmacología , Humanos , Indoles , Ratones , Ratones SCID , Morfolinas , Fosforilación/efectos de los fármacos , Fosforilación/genética , Piperazinas/farmacología , Pirazoles , Piridazinas , Pirimidinas/farmacología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Sulfonamidas , Sulfóxidos/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto
6.
PLoS One ; 6(4): e18772, 2011 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-21533282

RESUMEN

We employed the Cre recombinase/loxP system to create a mouse line in which PKA activity can be inhibited in any cell-type that expresses Cre recombinase. The mouse line carries a mutant Prkar1a allele encoding a glycine to aspartate substitution at position 324 in the carboxy-terminal cAMP-binding domain (site B). This mutation produces a dominant negative RIα regulatory subunit (RIαB) and leads to inhibition of PKA activity. Insertion of a loxP-flanked neomycin cassette in the intron preceding the site B mutation prevents expression of the mutant RIαB allele until Cre-mediated excision of the cassette occurs. Embryonic stem cells expressing RIαB demonstrated a reduction in PKA activity and inhibition of cAMP-responsive gene expression. Mice expressing RIαB in hepatocytes exhibited reduced PKA activity, normal fasting induced gene expression, and enhanced glucose disposal. Activation of the RIαB allele in vivo provides a novel system for the analysis of PKA function in physiology.


Asunto(s)
Proteínas Quinasas Dependientes de AMP Cíclico/genética , Genes Dominantes , Mutación , Alelos , Animales , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Células Madre Embrionarias/metabolismo , Glucosa/metabolismo , Integrasas/genética , Ratones , Reacción en Cadena de la Polimerasa
7.
ACS Med Chem Lett ; 2(5): 342-7, 2011 May 12.
Artículo en Inglés | MEDLINE | ID: mdl-24900315

RESUMEN

The V600E mutation of B-Raf kinase results in constitutive activation of the MAPK signaling pathway and is present in approximately 7% of all cancers. Using structure-based design, a novel series of pyrazolopyridine inhibitors of B-Raf(V600E) was developed. Optimization led to the identification of 3-methoxy pyrazolopyridines 17 and 19, potent, selective, and orally bioavailable agents that inhibited tumor growth in a mouse xenograft model driven by B-Raf(V600E) with no effect on body weight. On the basis of their in vivo efficacy and preliminary safety profiles, 17 and 19 were selected for further preclinical evaluation.

8.
J Neurosci ; 26(20): 5393-401, 2006 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-16707791

RESUMEN

Patterning of the mouse somatosensory cortex is unusually evident because of the presence of a "barrel field." Presynaptic serotonin and postsynaptic glutamate receptors regulate barrel formation, but little is known of the intracellular signaling pathways through which they act. To determine whether protein kinase A (PKA) plays a role in the development of the barrel field, we examined five viable PKA subunit-specific knock-out (KO) mouse lines for barrel field abnormalities. Barrels are present in these mice, but those lacking the RIIbeta subunit display significantly reduced contrast between the cell densities of barrel hollows and sides compared with wild-type animals. Thalamocortical afferent segregation in the posterior medial barrel subfield appeared normal, suggesting a postsynaptic site of gene action for the RIIbeta protein. Immunoelectron microscopy confirmed that RIIbeta was selectively localized to dendrites and dendritic spines. Mice lacking RIIbeta show reduced glutamate receptor A (GluRA) subunit insertion into the postsynaptic density in postnatal day 7 somatosensory cortex; however, GluRA KO mice developed normal barrels. Our results clearly demonstrate a role for postsynaptic PKA signaling pathways in barrel differentiation. They also demonstrate a clear dissociation between the regulation of GluRA trafficking by PKA and its role in barrel formation. Finally, although a role for PKA downstream of cAMP cannot be ruled out, these data suggest that PKA may not be the principle downstream target because none of the mutants showed a barrelless phenotype similar to that observed in adenylate cyclase type 1 KO mice. These results give insight into activity-dependent mechanisms that regulate barrel formation.


Asunto(s)
Tipificación del Cuerpo/genética , Diferenciación Celular/genética , Proteínas Quinasas Dependientes de AMP Cíclico/genética , Malformaciones del Sistema Nervioso/enzimología , Malformaciones del Sistema Nervioso/genética , Corteza Somatosensorial/anomalías , Corteza Somatosensorial/enzimología , Animales , Animales Recién Nacidos , AMP Cíclico/metabolismo , Espinas Dendríticas/metabolismo , Regulación del Desarrollo de la Expresión Génica/genética , Ratones , Ratones Noqueados , Vías Nerviosas/anomalías , Vías Nerviosas/enzimología , Subunidades de Proteína/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Membranas Sinápticas/genética , Membranas Sinápticas/metabolismo , Transmisión Sináptica/genética , Núcleos Talámicos Ventrales/anomalías , Núcleos Talámicos Ventrales/enzimología
9.
J Neurobiol ; 66(3): 256-72, 2006 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-16329126

RESUMEN

A number of in vitro studies suggest that many important developmental and functional events in the enteric nervous system are regulated by the intracellular signaling enzyme cAMP protein kinase A (PKA). To evaluate the in vivo significance of these observations, a Cre-inducible, dominant-negative, mutant regulatory subunit (RIalphaB) of PKA was activated in enteric neurons by either a Proteolipid protein-Cre transgene or a Hox11L1-Cre "knock-in" allele. In both models, RIalphaB activation resulted consistently in profound distension of the proximal small intestine within 2 weeks after birth. Intestinal transit of radio-opaque tracers was severely retarded in the double-transgenic animals, which died shortly after weaning. In the enteric nervous system, recombination was restricted to neurons as demonstrated by histochemical analysis and confocal microscopic colocalization of a Cre recombinase-dependent reporter gene with the neuronal marker Hu(C/D), in contrast with the glial marker S100. Histochemical analysis of beta-galactosidase expression and acetylcholinesterase activity, as well as neuronal counts, demonstrated that intestinal dysmotility was not associated with obvious malformation of the myenteric plexus. However, inhibition of PKA activity in enteric neurons disrupted the major motor complexes of isolated intestinal segments in vitro. These results provide strong evidence that PKA activity plays a critical role in enteric neurotransmission in vivo, and highlight neuronal PKA or related signaling molecules as potential therapeutic targets in gastrointestinal motility disorders.


Asunto(s)
Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Sistema Nervioso Entérico/fisiología , Motilidad Gastrointestinal/fisiología , Seudoobstrucción Intestinal/enzimología , Seudoobstrucción Intestinal/fisiopatología , Neuronas/enzimología , Animales , Western Blotting , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico , Proteínas Quinasas Dependientes de AMP Cíclico/genética , Modelos Animales de Enfermedad , Integrasas , Seudoobstrucción Intestinal/patología , Ratones , Ratones Transgénicos , Mutación , Fosforilación , Reacción en Cadena de la Polimerasa
10.
Genesis ; 43(3): 109-19, 2005 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-16155866

RESUMEN

Using the cre-loxP recombination system, we generated a line of mice expressing a constitutively active catalytic subunit of Protein Kinase A (PKA) in a temporally and spatially regulated fashion. In the absence of cre recombinase the modified catalytic subunit allele is functionally silent, but after recombination the mutant allele is expressed, resulting in enhanced PKA effects at basal cAMP levels. Mice expressing the modified protein in hepatocytes using albumin-cre transgenics show defects in glucose homeostasis, glycogen storage, fructose 2,6-bisphosphate levels, and induction of glucokinase mRNA during feeding. Similar to animals lacking glucokinase in the liver (Postic et al.: J Biol Chem 274:305-315, 1999), these mice also have defects in glucose-stimulated insulin secretion, a hallmark of Type II diabetes. The widespread expression of PKA and the involvement of this kinase in a myriad of signaling pathways suggest that these animals will provide critical tools for the study of PKA function in vivo.


Asunto(s)
Proteínas Quinasas Dependientes de AMP Cíclico/genética , Regulación de la Expresión Génica , Trastornos del Metabolismo de la Glucosa/metabolismo , Integrasas/genética , Animales , Secuencia de Bases , Glucemia/metabolismo , Proteína Quinasa Tipo II Dependiente de AMP Cíclico , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Marcación de Gen , Trastornos del Metabolismo de la Glucosa/genética , Prueba de Tolerancia a la Glucosa , Insulina/sangre , Insulina/metabolismo , Secreción de Insulina , Integrasas/metabolismo , Ratones , Mutagénesis Insercional , Mutación , ARN Mensajero/metabolismo , Transducción de Señal
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