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1.
Blood ; 140(20): 2113-2126, 2022 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-35704690

RESUMO

The BCL2 inhibitor venetoclax has been approved to treat different hematological malignancies. Because there is no common genetic alteration causing resistance to venetoclax in chronic lymphocytic leukemia (CLL) and B-cell lymphoma, we asked if epigenetic events might be involved in venetoclax resistance. Therefore, we employed whole-exome sequencing, methylated DNA immunoprecipitation sequencing, and genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 screening to investigate venetoclax resistance in aggressive lymphoma and high-risk CLL patients. We identified a regulatory CpG island within the PUMA promoter that is methylated upon venetoclax treatment, mediating PUMA downregulation on transcript and protein level. PUMA expression and sensitivity toward venetoclax can be restored by inhibition of methyltransferases. We can demonstrate that loss of PUMA results in metabolic reprogramming with higher oxidative phosphorylation and adenosine triphosphate production, resembling the metabolic phenotype that is seen upon venetoclax resistance. Although PUMA loss is specific for acquired venetoclax resistance but not for acquired MCL1 resistance and is not seen in CLL patients after chemotherapy-resistance, BAX is essential for sensitivity toward both venetoclax and MCL1 inhibition. As we found loss of BAX in Richter's syndrome patients after venetoclax failure, we defined BAX-mediated apoptosis to be critical for drug resistance but not for disease progression of CLL into aggressive diffuse large B-cell lymphoma in vivo. A compound screen revealed TRAIL-mediated apoptosis as a target to overcome BAX deficiency. Furthermore, antibody or CAR T cells eliminated venetoclax resistant lymphoma cells, paving a clinically applicable way to overcome venetoclax resistance.


Assuntos
Neoplasias Hematológicas , Leucemia Linfocítica Crônica de Células B , Linfoma Difuso de Grandes Células B , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas Reguladoras de Apoptose/genética , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Linfoma Difuso de Grandes Células B/patologia , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Epigênese Genética
2.
Cell Death Dis ; 15(5): 345, 2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38769311

RESUMO

Treatment-naïve small cell lung cancer (SCLC) is typically susceptible to standard-of-care chemotherapy consisting of cisplatin and etoposide recently combined with PD-L1 inhibitors. Yet, in most cases, SCLC patients develop resistance to first-line therapy and alternative therapies are urgently required to overcome this resistance. In this study, we tested the efficacy of dinaciclib, an FDA-orphan drug and inhibitor of the cyclin-dependent kinase (CDK) 9, among other CDKs, in SCLC. Furthermore, we report on a newly developed, highly specific CDK9 inhibitor, VC-1, with tumour-killing activity in SCLC. CDK9 inhibition displayed high killing potential in a panel of mouse and human SCLC cell lines. Mechanistically, CDK9 inhibition led to a reduction in MCL-1 and cFLIP anti-apoptotic proteins and killed cells, almost exclusively, by intrinsic apoptosis. While CDK9 inhibition did not synergise with chemotherapy, it displayed high efficacy in chemotherapy-resistant cells. In vivo, CDK9 inhibition effectively reduced tumour growth and improved survival in both autochthonous and syngeneic SCLC models. Together, this study shows that CDK9 inhibition is a promising therapeutic agent against SCLC and could be applied to chemo-refractory or resistant SCLC.


Assuntos
Quinase 9 Dependente de Ciclina , Indolizinas , Neoplasias Pulmonares , Compostos de Piridínio , Carcinoma de Pequenas Células do Pulmão , Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Quinase 9 Dependente de Ciclina/metabolismo , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/patologia , Humanos , Animais , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Linhagem Celular Tumoral , Camundongos , Compostos de Piridínio/farmacologia , Compostos de Piridínio/uso terapêutico , Indolizinas/farmacologia , Óxidos N-Cíclicos/farmacologia , Apoptose/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico
4.
Nat Commun ; 9(1): 697, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29449575

RESUMO

T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell malignancy. Here we integrated large-scale profiling data of alterations in gene expression, allelic copy number (CN), and nucleotide sequences in 111 well-characterized patients. Besides prominent signatures of T-cell activation and prevalent clonal variants, we also identify novel hot-spots for CN variability, fusion molecules, alternative transcripts, and progression-associated dynamics. The overall lesional spectrum of T-PLL is mainly annotated to axes of DNA damage responses, T-cell receptor/cytokine signaling, and histone modulation. We formulate a multi-dimensional model of T-PLL pathogenesis centered around a unique combination of TCL1 overexpression with damaging ATM aberrations as initiating core lesions. The effects imposed by TCL1 cooperate with compromised ATM toward a leukemogenic phenotype of impaired DNA damage processing. Dysfunctional ATM appears inefficient in alleviating elevated redox burdens and telomere attrition and in evoking a p53-dependent apoptotic response to genotoxic insults. As non-genotoxic strategies, synergistic combinations of p53 reactivators and deacetylase inhibitors reinstate such cell death execution.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Dano ao DNA , Epigênese Genética , Leucemia Prolinfocítica de Células T/genética , Proteínas Proto-Oncogênicas/genética , Adulto , Idoso , Animais , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica/métodos , Células HEK293 , Humanos , Estimativa de Kaplan-Meier , Leucemia Prolinfocítica de Células T/tratamento farmacológico , Leucemia Prolinfocítica de Células T/metabolismo , Masculino , Camundongos Transgênicos , Pessoa de Meia-Idade , Mutação , Proteínas Proto-Oncogênicas/metabolismo
5.
Leukemia ; 31(5): 1177-1186, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-27773933

RESUMO

Treatment resistance becomes a challenge at some point in the course of most patients with chronic lymphocytic leukemia (CLL). This applies to fludarabine-based regimens, and is also an increasing concern in the era of more targeted therapies. As cells with low-replicative activity rely on repair that triggers checkpoint-independent noncanonical pathways, we reasoned that targeting the nucleotide excision repair (NER) reaction addresses a vulnerability of CLL and might even synergize with fludarabine, which blocks the NER gap-filling step. We interrogated here especially the replication-independent transcription-coupled-NER ((TC)-NER) in prospective trial patients, primary CLL cultures, cell lines and mice. We screen selected (TC)-NER-targeting compounds as experimental (illudins) or clinically approved (trabectedin) drugs. They inflict transcription-stalling DNA lesions requiring TC-NER either for their removal (illudins) or for generation of lethal strand breaks (trabectedin). Genetically defined systems of NER deficiency confirmed their specificity. They selectively and efficiently induced cell death in CLL, irrespective of high-risk cytogenetics, IGHV status or clinical treatment history, including resistance. The substances induced ATM/p53-independent apoptosis and showed marked synergisms with fludarabine. Trabectedin additionally perturbed stromal-cell protection and showed encouraging antileukemic profiles even in aggressive and transforming murine CLL. This proof-of-principle study established (TC)-NER as a mechanism to be further exploited to resensitize CLL cells.


Assuntos
Reparo do DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Leucemia Linfocítica Crônica de Células B/genética , Transcrição Gênica , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios Clínicos como Assunto , Dioxóis/uso terapêutico , Sinergismo Farmacológico , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Camundongos , Tetra-Hidroisoquinolinas/uso terapêutico , Trabectedina , Células Tumorais Cultivadas , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico
7.
Cell Death Dis ; 6: e1764, 2015 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-25996291

RESUMO

The tumor suppressor p53 is mainly involved in the transcriptional regulation of a large number of growth-arrest- and apoptosis-related genes. However, a clear understanding of which factor/s influences the choice between these two opposing p53-dependent outcomes remains largely elusive. We have previously described that in response to DNA damage, the RNA polymerase II-binding protein Che-1/AATF transcriptionally activates p53. Here, we show that Che-1 binds directly to p53. This interaction essentially occurs in the first hours of DNA damage, whereas it is lost when cells undergo apoptosis in response to posttranscriptional modifications. Moreover, Che-1 sits in a ternary complex with p53 and the oncosuppressor Brca1. Accordingly, our analysis of genome-wide chromatin occupancy by p53 revealed that p53/Che1 interaction results in preferential transactivation of growth arrest p53 target genes over its pro-apoptotic target genes. Notably, exposure of Che-1(+/-) mice to ionizing radiations resulted in enhanced apoptosis of thymocytes, compared with WT mice. These results confirm Che-1 as an important regulator of p53 activity and suggest Che-1 to be a promising yet attractive drug target for cancer therapy.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Apoptose/genética , Proteína BRCA1/metabolismo , Pontos de Checagem do Ciclo Celular/genética , Proteínas Repressoras/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Linhagem Celular Tumoral , Dano ao DNA/genética , Reparo do DNA/genética , Ativação Enzimática/genética , Regulação da Expressão Gênica , Células HCT116 , Humanos , Células MCF-7 , Camundongos , Camundongos Transgênicos , Ligação Proteica/genética , Interferência de RNA , RNA Interferente Pequeno , Proteínas Repressoras/genética , Timócitos/patologia , Timócitos/efeitos da radiação , Ativação Transcricional/genética , Proteína Supressora de Tumor p53/genética
8.
Dtsch Med Wochenschr ; 138(3): 82-6, 2013 Jan.
Artigo em Alemão | MEDLINE | ID: mdl-23299342

RESUMO

The tumor suppressor p53 acts as a transcription factor downstream of many different stress-induced signaling pathways. Two major groups of p53-controlled genes can be distinguished. Those that mediate the initiation and maintenance of cell cycle checkpoints, and those driving apoptosis. An important determinant of the cellular reaction to DNA damage is the degree of genotoxic stress. The type of cellular response, which ranges from cell cycle arrest to apoptosis depends to a large extend on the severity of the genotoxic lesion. It remains largely unclear which molecular mechanisms govern the cellular decision between p53-driven cell cycle arrest and apoptosis. From a therapeutic perspective, this cellular decision is of utmost importance, as p53-driven apoptosis is therapeutically desired, when treating a malignant disease with DNA-damaging chemotherapy. However, a p53-driven cell cycle arrest might promote chemotherapy resistance, as it allows the tumor cells time to repair genotoxic lesions prior to the next cell division. Here, we summarize recent advances in our understanding of the molecular mechanisms controlling the functional outcome of p53 signaling. We further provide an outlook on the potential development of pharmacological interventions targeting the p53-regulating machinery to promote p53-driven apoptosis, while repressing p53-dependent cell cycle checkpoints.


Assuntos
Antineoplásicos/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Modelos Biológicos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Animais , Humanos
9.
Dtsch Med Wochenschr ; 136(30): 1526-30, 2011 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-21789751

RESUMO

Following DNA damage, cells activate a complex DNA-damage-response (DDR) signaling network to arrest the cell cycle, repair DNA and, if the extend of damage is beyond repair capacity, induce apoptosis. DDR genes are among the most commonly mutated genes in human cancer and it is believed that these lesions promote a "MUTATOR-PHENOTYPE" that fuels the runaway proliferation of cancer cells. However, these genetic lesions can also be seen as the "Achilles heel" of cancer. These tumor cell-specific vulnerabilities are of extraordinary clinical interest, since they allow genetically-guided novel therapeutic regimens for the treatment of cancer. Here, we discuss such a novel therapeutic concept - synthetic lethality. We focus on the first successful clinical applications of synthetic lethality for the treatment of different cancer entities. In addition, we give a brief review of recently developed, synthetic lethality-based approaches that are close to clinical testing.


Assuntos
Antineoplásicos/farmacologia , Apoptose/genética , Divisão Celular/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Transdução de Sinais/genética , Animais , Apoptose/efeitos dos fármacos , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Divisão Celular/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/genética , Análise Mutacional de DNA , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/genética , Epistasia Genética/efeitos dos fármacos , Epistasia Genética/genética , Feminino , Humanos , Oncogenes/efeitos dos fármacos , Oncogenes/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Fenótipo , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases/genética
10.
Leukemia ; 29(4): 981-4, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25376373
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