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1.
Proc Natl Acad Sci U S A ; 117(48): 30566-30576, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33203674

RESUMO

Aneuploidy, defined as whole chromosome gains and losses, is associated with poor patient prognosis in many cancer types. However, the condition causes cellular stress and cell cycle delays, foremost in G1 and S phase. Here, we investigate how aneuploidy causes both slow proliferation and poor disease outcome. We test the hypothesis that aneuploidy brings about resistance to chemotherapies because of a general feature of the aneuploid condition-G1 delays. We show that single chromosome gains lead to increased resistance to the frontline chemotherapeutics cisplatin and paclitaxel. Furthermore, G1 cell cycle delays are sufficient to increase chemotherapeutic resistance in euploid cells. Mechanistically, G1 delays increase drug resistance to cisplatin and paclitaxel by reducing their ability to damage DNA and microtubules, respectively. Finally, we show that our findings are clinically relevant. Aneuploidy correlates with slowed proliferation and drug resistance in the Cancer Cell Line Encyclopedia (CCLE) dataset. We conclude that a general and seemingly detrimental effect of aneuploidy, slowed proliferation, provides a selective benefit to cancer cells during chemotherapy treatment.


Assuntos
Aneuploidia , Antineoplásicos/farmacologia , Divisão Celular/efeitos dos fármacos , Divisão Celular/genética , Resistencia a Medicamentos Antineoplásicos/genética , Apoptose/efeitos dos fármacos , Apoptose/genética , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Cisplatino/farmacologia , Dano ao DNA/efeitos dos fármacos , Genes p53 , Humanos , Paclitaxel/farmacologia , Trissomia/genética
2.
Blood ; 133(1): 70-80, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30322870

RESUMO

Inhibition of the B-cell receptor (BCR) signaling pathway is a promising treatment strategy in multiple B-cell malignancies. However, the role of BCR blockade in diffuse large B-cell lymphoma (DLBCL) remains undefined. We recently characterized primary DLBCL subsets with distinct genetic bases for perturbed BCR/phosphoinositide 3-kinase (PI3K) signaling and dysregulated B-cell lymphoma 2 (BCL-2) expression. Herein, we explore the activity of PI3K inhibitors and BCL-2 blockade in a panel of functionally and genetically characterized DLBCL cell line models. A PI3K inhibitor with predominant α/δ activity, copanlisib, exhibited the highest cytotoxicity in all BCR-dependent DLBCLs. The proapoptotic effect of copanlisib was associated with DLBCL subtype-specific dysregulated expression of BCL-2 family members including harakiri (HRK) and its antiapoptotic partner BCL extra large (BCL-xL), BCL2 related protein A1, myeloid cell leukemia 1 (MCL-1), and BCL2 interacting mediator of cell death. Using functional BH3 profiling, we found that the cytotoxic activity of copanlisib was primarily mediated through BCL-xL and MCL-1-dependent mechanisms that might complement BCL-2 blockade. For these reasons, we evaluated single-agent activity of venetoclax in the DLBCLs and identified a subset with limited sensitivity to BCL-2 blockade despite having genetic bases of BCL-2 dysregulation. As these were largely BCR-dependent DLBCLs, we hypothesized that combined inhibition of PI3Kα/δ and BCL-2 would perturb BCR-dependent and BCL-2-mediated survival pathways. Indeed, we observed synergistic activity of copanlisib/venetoclax in BCR-dependent DLBCLs with genetic bases for BCL-2 dysregulation in vitro and confirmed these findings in a xenograft model. These results provide preclinical evidence for the rational combination of PI3Kα/δ and BCL-2 blockade in genetically defined DLBCLs.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Sinergismo Farmacológico , Linfoma Difuso de Grandes Células B/patologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Pirimidinas/farmacologia , Quinazolinas/farmacologia , Sulfonamidas/farmacologia , Animais , Antineoplásicos/farmacologia , Apoptose , Proliferação de Células , Feminino , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Cell Death Differ ; 27(3): 999-1007, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31332296

RESUMO

Inhibition of the anti-apoptotic machinery of cancer cells is a promising therapeutic approach that has driven the development of an important class of compounds termed "BH3 mimetics". These novel small molecules mimic BH3-only proteins by antagonizing the pro-survival function of anti-apoptotic proteins, thereby inducing apoptosis in cancer cells. To qualify as an authentic BH3 mimetic, a compound must function directly on the mitochondria of a cell of known anti-apoptotic dependence, must directly and selectively inhibit the anti-apoptotic protein with high-affinity binding, and must induce mitochondrial outer membrane permeabilization (MOMP) and apoptosis in a BAX/BAK-dependent manner. While many BH3 mimetics have entered clinical trials, the lack of a reliable validation assay to directly test the mitochondrial activity of new BH3 mimetic candidates has resulted in many misleading reports of agents touted as BH3 mimetics despite their off-target mechanisms of action. BH3 profiling probes the activity of a compound at the mitochondrial level by measuring cytochrome c release as a surrogate marker for MOMP. We propose a comprehensive biochemical toolkit consisting of BH3 profiling in parallel with high-throughput Annexin V/Hoechst viability testing to validate BH3 mimetic candidates. We tested our toolkit on eighteen different putative BH3 mimetics using a set of standardized cell lines of known anti-apoptotic dependence. Included in this set of cell lines is an apoptosis refractory BAX/BAK DKO control line to detect compounds that function independently of the BCL-2 family. Taken together, this rapid, efficient means of testing will prove advantageous as the demand for BH3 mimetics increases, particularly in the quest to identify and develop more potent MCL-1 inhibitors for use in the clinic. We strongly urge researchers utilizing BH3 mimetics in their work to use the potent and selective compounds identified with this validation toolkit instead of those lacking such potency and selectivity.


Assuntos
Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Morte Celular/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Ligação Proteica/efeitos dos fármacos , Proteína X Associada a bcl-2/metabolismo
5.
Cell Death Dis ; 10(8): 571, 2019 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-31358732

RESUMO

Deregulated cell death pathways contribute to leukemogenesis and treatment failure in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Intrinsic apoptosis signaling is regulated by different proapoptotic and antiapoptotic molecules: proapoptotic BCL-2 homology domain 3 (BH3) proteins activate prodeath molecules leading to cellular death, while antiapoptotic molecules including B-cell lymphoma 2 (BCL-2) prevent activation of prodeath proteins and counter-regulate apoptosis induction. Inhibition of these antiapoptotic regulators has become a promising strategy for anticancer treatment, but variable anticancer activities in different malignancies indicate the need for upfront identification of responsive patients. Here, we investigated the activity of the BCL-2 inhibitor venetoclax (VEN, ABT-199) in B-cell precursor acute lymphoblastic leukemia and found heterogeneous sensitivities in BCP-ALL cell lines and in a series of patient-derived primografts. To identify parameters of sensitivity and resistance, we evaluated genetic aberrations, gene-expression profiles, expression levels of apoptosis regulators, and functional apoptosis parameters analyzed by mitochondrial profiling using recombinant BH3-like peptides. Importantly, ex vivo VEN sensitivity was most accurately associated with functional BCL-2 dependence detected by BH3 profiling. Modeling clinical application of VEN in a preclinical trial in a set of individual ALL primografts, we identified that leukemia-free survival of VEN treated mice was precisely determined by functional BCL-2 dependence. Moreover, the predictive value of ex vivo measured functional BCL-2 dependence for preclinical in vivo VEN response was confirmed in an independent set of primograft ALL including T- and high risk-ALL. Thus, integrative analysis of the apoptosis signaling indicating mitochondrial addiction to BCL-2 accurately predicts antileukemia activity of VEN, robustly identifies VEN-responsive patients, and provides information for stratification and clinical guidance in future clinical applications of VEN in patients with ALL.


Assuntos
Apoptose/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Sulfonamidas/farmacologia , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/patologia , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Xenoenxertos , Humanos , Masculino , Camundongos , Mitocôndrias/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Transdução de Sinais/efeitos dos fármacos
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