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1.
Oncotarget ; 7(38): 61544-61561, 2016 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-27557495

RESUMEN

Chromosomal Instability (CIN) is regarded as a unifying feature of heterogeneous tumor populations, driving intratumoral heterogeneity. Polo-Like Kinase 1 (PLK1), a serine-threonine kinase that is often overexpressed across multiple tumor types, is one of the key regulators of CIN and is considered as a potential therapeutic target. However, targeting PLK1 has remained a challenge due to the off-target effects caused by the inhibition of other members of the polo-like family. Here we use synthetic dosage lethality (SDL), where the overexpression of PLK1 is lethal only when another, normally non-lethal, mutation or deletion is present. Rather than directly inhibiting PLK1, we found that inhibition of PP2A causes selective lethality to PLK1-overexpressing breast, pancreatic, ovarian, glioblastoma, and prostate cancer cells. As PP2A is widely regarded as a tumor suppressor, we resorted to gene expression datasets from cancer patients to functionally dissect its therapeutic relevance. We identified two major classes of PP2A subunits that negatively correlated with each other. Interestingly, most mitotic regulators, including PLK1, exhibited SDL interactions with only one class of PP2A subunits (PPP2R1A, PPP2R2D, PPP2R3B, PPP2R5B and PPP2R5D). Validation studies and other functional cell-based assays showed that inhibition of PPP2R5D affects both levels of phospho-Rb as well as sister chromatid cohesion in PLK1-overexpressing cells. Finally, analysis of clinical data revealed that patients with high expression of mitotic regulators and low expression of Class I subunits of PP2A improved survival. Overall, these observations point to a context-dependent role of PP2A that warrants further exploration for therapeutic benefits.


Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Inestabilidad Cromosómica/efectos de los fármacos , Genes Supresores de Tumor/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Proteína Fosfatasa 2/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Cantaridina/farmacología , Cantaridina/uso terapéutico , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/genética , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Técnicas de Silenciamiento del Gen , Células HCT116 , Humanos , Mitosis/efectos de los fármacos , Mutación , Neoplasias/genética , Neoplasias/patología , Fosforilación , Proteína Fosfatasa 2/genética , Proteína Fosfatasa 2/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/genética , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Proteínas de Unión a Retinoblastoma/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Quinasa Tipo Polo 1
2.
Oncotarget ; 7(31): 50027-50042, 2016 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-27418135

RESUMEN

Application of tumor genome sequencing has identified numerous loss-of-function alterations in cancer cells. While these alterations are difficult to target using direct interventions, they may be attacked with the help of the synthetic lethality (SL) approach. In this approach, inhibition of one gene causes lethality only when another gene is also completely or partially inactivated. The EPHB6 receptor tyrosine kinase has been shown to have anti-malignant properties and to be downregulated in multiple cancers, which makes it a very attractive target for SL applications. In our work, we used a genome-wide SL screen combined with expression and interaction network analyses, and identified the SRC kinase as a SL partner of EPHB6 in triple-negative breast cancer (TNBC) cells. Our experiments also reveal that this SL interaction can be targeted by small molecule SRC inhibitors, SU6656 and KX2-391, and can be used to improve elimination of human TNBC tumors in a xenograft model. Our observations are of potential practical importance, since TNBC is an aggressive heterogeneous malignancy with a very high rate of patient mortality due to the lack of targeted therapies, and our work indicates that FDA-approved SRC inhibitors may potentially be used in a personalized manner for treating patients with EPHB6-deficient TNBC. Our findings are also of a general interest, as EPHB6 is downregulated in multiple malignancies and our data serve as a proof of principle that EPHB6 deficiency may be targeted by small molecule inhibitors in the SL approach.


Asunto(s)
Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/terapia , Receptores de la Familia Eph/metabolismo , Mutaciones Letales Sintéticas , Neoplasias de la Mama Triple Negativas/metabolismo , Familia-src Quinasas/metabolismo , Acetamidas/química , Animales , Muerte Celular , Línea Celular Tumoral , Membrana Celular/metabolismo , Femenino , Colorantes Fluorescentes/química , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Inmunohistoquímica , Indoles/química , Ratones , Ratones Endogámicos NOD , Ratones SCID , Morfolinas , Piridinas/química , ARN Interferente Pequeño/metabolismo , Sulfonamidas/química , Ensayos Antitumor por Modelo de Xenoinjerto
3.
Trends Mol Med ; 20(12): 704-15, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25446836

RESUMEN

The most commonly used therapies for cancer involve delivering high doses of radiation or toxic chemicals to the patient that also cause substantial damage to normal tissue. To overcome this, researchers have recently resorted to a basic biological concept called 'synthetic lethality' (SL) that takes advantage of interactions between gene pairs. The identification of SL interactions is of considerable therapeutic interest because if a particular gene is SL with a tumor-causing mutation, then the targeting that gene carries therapeutic advantages. Mapping these interactions in the context of human cancer cells could hold the key to effective, targeted cancer treatments. In this review, we cover the recent advances that aim to identify these SL interactions using unbiased genetic screens.


Asunto(s)
Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/genética , Neoplasias/genética , Biología de Sistemas/métodos , Línea Celular Tumoral , Mapeo Cromosómico , Estudios de Asociación Genética , Pruebas Genéticas , Terapia Genética , Humanos , Modelos Genéticos , Familia de Multigenes , Mutación , Neoplasias/terapia , Interferencia de ARN
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