RESUMEN
Conventional therapies for patients with T-cell prolymphocytic leukemia (T-PLL), such as cytotoxic chemotherapy and alemtuzumab, have limited efficacy and considerable toxicity. Several novel agent classes have demonstrated preclinical activity in T-PLL, including inhibitors of the JAK/STAT and T-cell receptor pathways, as well as histone deacetylase (HDAC) inhibitors. Recently, the BCL-2 inhibitor venetoclax also showed some clinical activity in T-PLL. We sought to characterize functional apoptotic dependencies in T-PLL to identify a novel combination therapy in this disease. Twenty-four samples from patients with primary T-PLL were studied by using BH3 profiling, a functional assay to assess the propensity of a cell to undergo apoptosis (priming) and the relative dependence of a cell on different antiapoptotic proteins. Primary T-PLL cells had a relatively low level of priming for apoptosis and predominantly depended on BCL-2 and MCL-1 proteins for survival. Selective pharmacologic inhibition of BCL-2 or MCL-1 induced cell death in primary T-PLL cells. Targeting the JAK/STAT pathway with the JAK1/2 inhibitor ruxolitinib or HDAC with belinostat both independently increased dependence on BCL-2 but not MCL-1, thereby sensitizing T-PLL cells to venetoclax. Based on these results, we treated 2 patients with refractory T-PLL with a combination of venetoclax and ruxolitinib. We observed a deep response in JAK3-mutated T-PLL and a stabilization of the nonmutated disease. Our functional, precision-medicine-based approach identified inhibitors of HDAC and the JAK/STAT pathway as promising combination partners for venetoclax, warranting a clinical exploration of such combinations in T-PLL.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Leucemia Prolinfocítica de Células T/tratamiento farmacológico , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Proteínas de Neoplasias , Anciano , Anciano de 80 o más Años , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Femenino , Humanos , Leucemia Prolinfocítica de Células T/metabolismo , Leucemia Prolinfocítica de Células T/patología , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/metabolismo , Nitrilos/farmacología , Pirazoles/farmacología , Pirimidinas/farmacología , Sulfonamidas/farmacologíaRESUMEN
Bcl-2 phosphorylation at serine-70 (S70pBcl2) confers resistance against drug-induced apoptosis. Nevertheless, its specific mechanism in driving drug-resistance remains unclear. We present evidence that S70pBcl2 promotes cancer cell survival by acting as a redox sensor and modulator to prevent oxidative stress-induced DNA damage and execution. Increased S70pBcl2 levels are inversely correlated with DNA damage in chronic lymphocytic leukemia (CLL) and lymphoma patient-derived primary cells as well as in reactive oxygen species (ROS)- or chemotherapeutic drug-treated cell lines. Bioinformatic analyses suggest that S70pBcl2 is associated with lower median overall survival in lymphoma patients. Empirically, sustained expression of the redox-sensitive S70pBcl2 prevents oxidative stress-induced DNA damage and cell death by suppressing mitochondrial ROS production. Using cell lines and lymphoma primary cells, we further demonstrate that S70pBcl2 reduces the interaction of Bcl-2 with the mitochondrial complex-IV subunit-5A, thereby reducing mitochondrial complex-IV activity, respiration and ROS production. Notably, targeting S70pBcl2 with the phosphatase activator, FTY720, is accompanied by an enhanced drug-induced DNA damage and cell death in CLL primary cells. Collectively, we provide a novel facet of the anti-apoptotic Bcl-2 by demonstrating that its phosphorylation at serine-70 functions as a redox sensor to prevent drug-induced oxidative stress-mediated DNA damage and execution with potential therapeutic implications.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Linfoma/tratamiento farmacológico , Mitocondrias/metabolismo , Estrés Oxidativo/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/genética , Apoptosis/genética , Proliferación Celular/genética , Cisplatino/farmacología , Daño del ADN/efectos de los fármacos , Doxorrubicina/farmacología , Resistencia a Antineoplásicos/genética , Etopósido/farmacología , Fluorouracilo/farmacología , Humanos , Células Jurkat , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/patología , Linfoma/genética , Linfoma/patología , Mitocondrias/efectos de los fármacos , Mitocondrias/genética , Oxidación-Reducción/efectos de los fármacos , Fosforilación/efectos de los fármacos , Cultivo Primario de Células , Especies Reactivas de Oxígeno/metabolismo , Serina/genéticaAsunto(s)
Leucemia Prolinfocítica de Células T , Leucemia Prolinfocítica , Linfoma , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Alemtuzumab/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes , Epigénesis Genética , Humanos , Leucemia Prolinfocítica de Células T/genética , Masculino , Sulfonamidas , Linfocitos TRESUMEN
The identification of targetable vulnerabilities in the context of therapeutic resistance is a key challenge in cancer treatment. We detected pervasive aberrant splicing as a characteristic feature of chronic lymphocytic leukemia (CLL), irrespective of splicing factor mutation status, which was associated with sensitivity to the spliceosome modulator, E7107. Splicing modulation affected CLL survival pathways, including members of the B cell lymphoma-2 (BCL2) family of proteins, remodeling antiapoptotic dependencies of human and murine CLL cells. E7107 treatment decreased myeloid cell leukemia-1 (MCL1) dependence and increased BCL2 dependence, sensitizing primary human CLL cells and venetoclax-resistant CLL-like cells from an Eµ-TCL1-based adoptive transfer murine model to treatment with the BCL2 inhibitor venetoclax. Our data provide preclinical rationale to support the combination of venetoclax with splicing modulators to reprogram apoptotic dependencies in CLL for treating venetoclax-resistant CLL cases.
Asunto(s)
Empalme Alternativo/efectos de los fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Compuestos Epoxi/farmacología , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Macrólidos/farmacología , Sulfonamidas/farmacología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Apoptosis/genética , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Ensayos de Selección de Medicamentos Antitumorales , Compuestos Epoxi/uso terapéutico , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/patología , Macrólidos/uso terapéutico , Masculino , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Mutación , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/antagonistas & inhibidores , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Fosfoproteínas/genética , Cultivo Primario de Células , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Factores de Empalme de ARN/genética , Empalmosomas/efectos de los fármacos , Empalmosomas/metabolismo , Sulfonamidas/uso terapéutico , Tiofenos/farmacología , Tiofenos/uso terapéuticoRESUMEN
Dysregulation of the B-cell leukemia/lymphoma-2 (BCL-2) family of proteins of the intrinsic apoptotic pathway is fundamental to the pathophysiology of many hematologic malignancies. The BCL-2 family consists of regulatory proteins that either induce apoptosis (proapoptotic) or inhibit it (prosurvival). BCL-2, myeloid cell leukemia-1, and B-cell lymphoma-extra large are prosurvival proteins that are prime targets for anticancer therapy, and molecules targeting each are in various stages of preclinical and clinical development. The US Food and Drug Administration (FDA)-approved BCL-2 inhibitor venetoclax was first proven to be highly effective in chronic lymphocytic leukemia and some B-cell non-Hodgkin lymphoma subtypes. Subsequently, venetoclax was found to be active clinically against a diverse array of hematologic malignancies including multiple myeloma, acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, and others. Here, we give a brief introduction to BCL-2 family biology and the mechanism of action of BCL-2 Homology 3 (BH3) mimetics, and provide an overview of the clinical data for therapeutically targeting prosurvival proteins in hematologic malignancies, with a focus on BCL-2 inhibition. To prioritize novel agent combinations and predict responders, we discuss the utility of functional assays such as BH3 profiling. Finally, we provide a perspective on how therapies targeting BCL-2 family proteins may be optimally implemented into future therapeutic regimens for hematologic malignancies.
Asunto(s)
Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Neoplasias Hematológicas/tratamiento farmacológico , Terapia Molecular Dirigida/métodos , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Animales , Antineoplásicos/farmacología , Resistencia a Antineoplásicos , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patología , Humanos , Leucemia/tratamiento farmacológico , Leucemia/metabolismo , Leucemia/patología , Linfoma/tratamiento farmacológico , Linfoma/metabolismo , Linfoma/patología , Mapas de Interacción de Proteínas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/metabolismoRESUMEN
BACKGROUND: Optimal treatment strategy for the oldest patients with diffuse large B-cell lymphoma (DLBCL) remains controversial, as this group often is precluded from clinical trials, and population-based studies are limited. METHODS: All Danish DLBCL-patients ≥75 years diagnosed from 2003 to 2012 were identified, using the Danish National Lymphoma Registry (LYFO). Information regarding baseline characteristics, treatment, comorbidities and outcomes was retrieved from LYFO, the Danish National health registries and medical records. Patients were stratified by age (75-79; 80-84 and 85 + years), comorbidity score and treatment modality (standard treatment [R-CHOP/CHOP-like], less intensive regimens or palliative treatment). FINDINGS: A total of 1011 patients were included. Standard treatment was initiated in 64%, ranging from 83% among patients aged 75-79 years to 32% among patient aged 85 + years. With standard treatment, median overall survival (OS) estimates were 4·6, 2·6, and 1·9 years for the age groups 75-79, 80-84 and 85+ years. Among patient aged 75-79 and 80-84 years, OS was superior with standard treatment, although high comorbidity scores attenuated this association. Among patients aged 85+ years, survival was not influenced by treatment intensity. Patients ≥80 years had similar OS regardless of intended (R-)CHOP dosing, whereas patients of 75-79 years scheduled for full dose had higher OS. Standard treatment was not associated with increased hospitalisation. INTERPRETATION: Standard treatment is feasible with good outcomes in a large proportion of elderly DLBCL-patients. Planned dose reduction in patients aged ≥80 years had no negative impact on OS.