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1.
Mol Cancer Ther ; 21(5): 821-830, 2022 05 04.
Artículo en Inglés | MEDLINE | ID: mdl-35247925

RESUMEN

NRG1 fusions are recurrent somatic genome alterations occurring across several tumor types, including invasive mucinous lung adenocarcinomas and pancreatic ductal adenocarcinomas and are potentially actionable genetic alterations in these cancers. We initially discovered CD74-NRG1 as the first NRG1 fusion in lung adenocarcinomas, and many additional fusion partners have since been identified. Here, we present the first CD74-NRG1 transgenic mouse model and provide evidence that ubiquitous expression of the CD74-NRG1 fusion protein in vivo leads to tumor development at high frequency. Furthermore, we show that ERBB2:ERBB3 heterodimerization is a mechanistic event in transformation by CD74-NRG1 binding physically to ERBB3 and that CD74-NRG1-expressing cells proliferate independent of supplemented NRG1 ligand. Thus, NRG1 gene fusions are recurrent driver oncogenes that cause oncogene dependency. Consistent with these findings, patients with NRG1 fusion-positive cancers respond to therapy targeting the ERBB2:ERBB3 receptors.


Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Animales , Carcinogénesis/genética , Humanos , Ratones , Neurregulina-1/genética , Oncogenes , Receptor ErbB-2/genética , Receptor ErbB-3/genética
2.
Nat Commun ; 12(1): 5505, 2021 09 17.
Artículo en Inglés | MEDLINE | ID: mdl-34535668

RESUMEN

Kinase inhibitors suppress the growth of oncogene driven cancer but also enforce the selection of treatment resistant cells that are thought to promote tumor relapse in patients. Here, we report transcriptomic and functional genomics analyses of cells and tumors within their microenvironment across different genotypes that persist during kinase inhibitor treatment. We uncover a conserved, MAPK/IRF1-mediated inflammatory response in tumors that undergo stemness- and senescence-associated reprogramming. In these tumor cells, activation of the innate immunity sensor RIG-I via its agonist IVT4, triggers an interferon and a pro-apoptotic response that synergize with concomitant kinase inhibition. In humanized lung cancer xenografts and a syngeneic Egfr-driven lung cancer model these effects translate into reduction of exhausted CD8+ T cells and robust tumor shrinkage. Overall, the mechanistic understanding of MAPK/IRF1-mediated intratumoral reprogramming may ultimately prolong the efficacy of targeted drugs in genetically defined cancer patients.


Asunto(s)
Proteína 58 DEAD Box/metabolismo , Inmunidad Innata , Inflamación/patología , Sistema de Señalización de MAP Quinasas , Neoplasias/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Receptores Inmunológicos/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Puntos de Control del Ciclo Celular/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Citocinas/metabolismo , Receptores ErbB/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Evasión Inmune/efectos de los fármacos , Inmunidad Innata/efectos de los fármacos , Factor 1 Regulador del Interferón/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Neoplasias/patología , Oncogenes , Transducción de Señal/efectos de los fármacos
3.
Nat Commun ; 12(1): 2048, 2021 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-33824345

RESUMEN

Loss of TP53 and RB1 in treatment-naïve small cell lung cancer (SCLC) suggests selective pressure to inactivate cell death pathways prior to therapy. Yet, which of these pathways remain available in treatment-naïve SCLC is unknown. Here, through systemic analysis of cell death pathway availability in treatment-naïve SCLC, we identify non-neuroendocrine (NE) SCLC to be vulnerable to ferroptosis through subtype-specific lipidome remodeling. While NE SCLC is ferroptosis resistant, it acquires selective addiction to the TRX anti-oxidant pathway. In experimental settings of non-NE/NE intratumoral heterogeneity, non-NE or NE populations are selectively depleted by ferroptosis or TRX pathway inhibition, respectively. Preventing subtype plasticity observed under single pathway targeting, combined treatment kills established non-NE and NE tumors in xenografts, genetically engineered mouse models of SCLC and patient-derived cells, and identifies a patient subset with drastically improved overall survival. These findings reveal cell death pathway mining as a means to identify rational combination therapies for SCLC.


Asunto(s)
Ferroptosis , Tumores Neuroendocrinos/patología , Carcinoma Pulmonar de Células Pequeñas/patología , Animales , Antioxidantes/metabolismo , Apoptosis , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Supervivencia Celular , Humanos , Metabolismo de los Lípidos , Masculino , Ratones Desnudos , Modelos Biológicos , Necroptosis , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Fosfolípidos/metabolismo , Pronóstico , Tiorredoxinas/metabolismo
4.
Nat Commun ; 10(1): 3485, 2019 08 02.
Artículo en Inglés | MEDLINE | ID: mdl-31375684

RESUMEN

MYC paralogs are frequently activated in small cell lung cancer (SCLC) but represent poor drug targets. Thus, a detailed mapping of MYC-paralog-specific vulnerabilities may help to develop effective therapies for SCLC patients. Using a unique cellular CRISPR activation model, we uncover that, in contrast to MYCN and MYCL, MYC represses BCL2 transcription via interaction with MIZ1 and DNMT3a. The resulting lack of BCL2 expression promotes sensitivity to cell cycle control inhibition and dependency on MCL1. Furthermore, MYC activation leads to heightened apoptotic priming, intrinsic genotoxic stress and susceptibility to DNA damage checkpoint inhibitors. Finally, combined AURK and CHK1 inhibition substantially prolongs the survival of mice bearing MYC-driven SCLC beyond that of combination chemotherapy. These analyses uncover MYC-paralog-specific regulation of the apoptotic machinery with implications for genotype-based selection of targeted therapeutics in SCLC patients.


Asunto(s)
Apoptosis/genética , Regulación Neoplásica de la Expresión Génica/genética , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Carcinoma Pulmonar de Células Pequeñas/genética , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Sistemas CRISPR-Cas/genética , Línea Celular Tumoral , Daño del ADN/efectos de los fármacos , Daño del ADN/genética , Modelos Animales de Enfermedad , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HEK293 , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Ratones , Terapia Molecular Dirigida/métodos , Proteínas Proto-Oncogénicas c-myc/genética , ARN Interferente Pequeño/metabolismo , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico
5.
Nat Commun ; 9(1): 4655, 2018 11 07.
Artículo en Inglés | MEDLINE | ID: mdl-30405134

RESUMEN

The emergence of acquired resistance against targeted drugs remains a major clinical challenge in lung adenocarcinoma patients. In a subgroup of these patients we identified an association between selection of EGFRT790M-negative but EGFRG724S-positive subclones and osimertinib resistance. We demonstrate that EGFRG724S limits the activity of third-generation EGFR inhibitors both in vitro and in vivo. Structural analyses and computational modeling indicate that EGFRG724S mutations may induce a conformation of the glycine-rich loop, which is incompatible with the binding of third-generation TKIs. Systematic inhibitor screening and in-depth kinetic profiling validate these findings and show that second-generation EGFR inhibitors retain kinase affinity and overcome EGFRG724S-mediated resistance. In the case of afatinib this profile translates into a robust reduction of colony formation and tumor growth of EGFRG724S-driven cells. Our data provide a mechanistic basis for the osimertinib-induced selection of EGFRG724S-mutant clones and a rationale to treat these patients with clinically approved second-generation EGFR inhibitors.


Asunto(s)
Resistencia a Antineoplásicos/efectos de los fármacos , Receptores ErbB/antagonistas & inhibidores , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Acrilamidas , Compuestos de Anilina , Animales , Línea Celular Tumoral , Progresión de la Enfermedad , Receptores ErbB/química , Receptores ErbB/metabolismo , Femenino , Humanos , Cinética , Ratones , Ratones Desnudos , Mutación/genética , Células 3T3 NIH , Piperazinas/química , Unión Proteica/efectos de los fármacos , Conformación Proteica , Inhibidores de Proteínas Quinasas/química
6.
Cell Rep ; 20(12): 2833-2845, 2017 Sep 19.
Artículo en Inglés | MEDLINE | ID: mdl-28930680

RESUMEN

Kinase inhibitors represent the backbone of targeted cancer therapy, yet only a limited number of oncogenic drivers are directly druggable. By interrogating the activity of 1,505 kinase inhibitors, we found that BRD4-NUT-rearranged NUT midline carcinoma (NMC) cells are specifically killed by CDK9 inhibition (CDK9i) and depend on CDK9 and Cyclin-T1 expression. We show that CDK9i leads to robust induction of apoptosis and of markers of DNA damage response in NMC cells. While both CDK9i and bromodomain inhibition over time result in reduced Myc protein expression, only bromodomain inhibition induces cell differentiation and a p21-induced cell-cycle arrest in these cells. Finally, RNA-seq and ChIP-based analyses reveal a BRD4-NUT-specific CDK9i-induced perturbation of transcriptional elongation. Thus, our data provide a mechanistic basis for the genotype-dependent vulnerability of NMC cells to CDK9i that may be of relevance for the development of targeted therapies for NMC patients.


Asunto(s)
Terapia Molecular Dirigida , Neoplasias/enzimología , Neoplasias/patología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas de Ciclo Celular , Línea Celular Tumoral , Ciclina T/metabolismo , Quinasa 9 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 9 Dependiente de la Ciclina/metabolismo , Células HEK293 , Ensayos Analíticos de Alto Rendimiento , Humanos , Neoplasias/genética , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/metabolismo , Inhibidores de Proteínas Quinasas/química , ARN Polimerasa II/metabolismo , Elongación de la Transcripción Genética/efectos de los fármacos , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismo , Transcripción Genética/efectos de los fármacos
7.
Sci Transl Med ; 9(394)2017 06 14.
Artículo en Inglés | MEDLINE | ID: mdl-28615362

RESUMEN

Oncogenic fusion events have been identified in a broad range of tumors. Among them, RET rearrangements represent distinct and potentially druggable targets that are recurrently found in lung adenocarcinomas. We provide further evidence that current anti-RET drugs may not be potent enough to induce durable responses in such tumors. We report that potent inhibitors, such as AD80 or ponatinib, that stably bind in the DFG-out conformation of RET may overcome these limitations and selectively kill RET-rearranged tumors. Using chemical genomics in conjunction with phosphoproteomic analyses in RET-rearranged cells, we identify the CCDC6-RETI788N mutation and drug-induced mitogen-activated protein kinase pathway reactivation as possible mechanisms by which tumors may escape the activity of RET inhibitors. Our data provide mechanistic insight into the druggability of RET kinase fusions that may be of help for the development of effective therapies targeting such tumors.


Asunto(s)
Adenocarcinoma/metabolismo , Reordenamiento Génico/genética , Neoplasias Pulmonares/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-ret/genética , Adenocarcinoma del Pulmón , Animales , Línea Celular Tumoral , Proteínas del Citoesqueleto/genética , Resistencia a Antineoplásicos/genética , Reordenamiento Génico/efectos de los fármacos , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , Imidazoles/farmacología , Ratones , Mutación , Células 3T3 NIH , Piridazinas/farmacología
8.
Nucleic Acids Res ; 44(17): 8144-52, 2016 09 30.
Artículo en Inglés | MEDLINE | ID: mdl-27257073

RESUMEN

Attenuation of ribosome biogenesis in suboptimal growth environments is crucial for cellular homeostasis and genetic integrity. Here, we show that shutdown of rRNA synthesis in response to elevated temperature is brought about by mechanisms that target both the RNA polymerase I (Pol I) transcription machinery and the epigenetic signature of the rDNA promoter. Upon heat shock, the basal transcription factor TIF-IA is inactivated by inhibition of CK2-dependent phosphorylations at Ser170/172. Attenuation of pre-rRNA synthesis in response to heat stress is accompanied by upregulation of PAPAS, a long non-coding RNA (lncRNA) that is transcribed in antisense orientation to pre-rRNA. PAPAS interacts with CHD4, the adenosine triphosphatase subunit of NuRD, leading to deacetylation of histones and movement of the promoter-bound nucleosome into a position that is refractory to transcription initiation. The results exemplify how stress-induced inactivation of TIF-IA and lncRNA-dependent changes of chromatin structure ensure repression of rRNA synthesis in response to thermo-stress.


Asunto(s)
Respuesta al Choque Térmico/genética , Nucleosomas/metabolismo , Proteínas del Complejo de Iniciación de Transcripción Pol1/metabolismo , ARN Largo no Codificante/metabolismo , ARN Ribosómico/biosíntesis , Animales , Quinasa de la Caseína II/metabolismo , Ensamble y Desensamble de Cromatina , Células HEK293 , N-Metiltransferasa de Histona-Lisina , Humanos , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/metabolismo , Ratones , Células 3T3 NIH , Fosforilación , Regiones Promotoras Genéticas , Transcripción Genética
9.
Nucleic Acids Res ; 40(Database issue): D242-51, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22110040

RESUMEN

Linear motifs are short, evolutionarily plastic components of regulatory proteins and provide low-affinity interaction interfaces. These compact modules play central roles in mediating every aspect of the regulatory functionality of the cell. They are particularly prominent in mediating cell signaling, controlling protein turnover and directing protein localization. Given their importance, our understanding of motifs is surprisingly limited, largely as a result of the difficulty of discovery, both experimentally and computationally. The Eukaryotic Linear Motif (ELM) resource at http://elm.eu.org provides the biological community with a comprehensive database of known experimentally validated motifs, and an exploratory tool to discover putative linear motifs in user-submitted protein sequences. The current update of the ELM database comprises 1800 annotated motif instances representing 170 distinct functional classes, including approximately 500 novel instances and 24 novel classes. Several older motif class entries have been also revisited, improving annotation and adding novel instances. Furthermore, addition of full-text search capabilities, an enhanced interface and simplified batch download has improved the overall accessibility of the ELM data. The motif discovery portion of the ELM resource has added conservation, and structural attributes have been incorporated to aid users to discriminate biologically relevant motifs from stochastically occurring non-functional instances.


Asunto(s)
Secuencias de Aminoácidos , Bases de Datos de Proteínas , Gráficos por Computador , Enfermedad/genética , Eucariontes , Análisis de Secuencia de Proteína , Interfaz Usuario-Computador , Proteínas Virales/química
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