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1.
Nat Commun ; 11(1): 4249, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32843618

RESUMO

Aberrant cell cycle machinery and loss of the CDKN2A tumor suppressor locus make CDK4/6 a potential target in pancreatic ductal adenocarcinoma (PDAC). However, a vast majority of PDAC cases do not harbor a durable response to monotherapy of CDK4/6 inhibitor. Utilizing remote loading to co-encapsulate CDK4/6 inhibitor palbociclib (PAL) and an autophagy inhibitor hydroxychloroquine (HCQ), we demonstrate a ratiometrically designed mesoporous silica nanoformulation with synergistic efficacy in subcutaneous and orthotopic PDAC mouse models. The synergism is attributed to the effective intratumoral buildup of PAL/HCQ, which otherwise exhibit distinctly different circulatory and biodistribution profile. PAL/HCQ co-delivery nanoparticles lead to the most effective shrinkage of PDAC compared to various controls, including free drug mixture. Immunohistochemistry reveals that PAL/HCQ co-delivery nanoparticles trigger anti-apoptotic pathway after repetitive intravenous administrations in mice. When combined with a Bcl inhibitor, the performance of co-delivery nanoparticles is further improved, leading to a long-lasting anti-PDAC effect in vivo.


Assuntos
Autofagia/efeitos dos fármacos , Carcinoma Ductal Pancreático/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Sistemas de Liberação de Medicamentos , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Sinergismo Farmacológico , Humanos , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/química , Hidroxicloroquina/farmacologia , Camundongos , Nanopartículas/administração & dosagem , Nanopartículas/química , Piperazinas/administração & dosagem , Piperazinas/química , Piperazinas/farmacologia , Piridinas/administração & dosagem , Piridinas/química , Piridinas/farmacologia , Dióxido de Silício/administração & dosagem , Dióxido de Silício/química , Dióxido de Silício/farmacologia , Resultado do Tratamento
2.
Eur J Cancer ; 136: 99-106, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32659475

RESUMO

BACKGROUND: In light of the coronavirus disease 2019 (COVID-19) pandemic, cancer centres in the United Kingdom and Europe re-organised their services at an unprecedented pace, and many patients with cancer have had their treatments severely disrupted. Patients with cancer were considered at high risk on sparse evidence, and despite a small number of emerging observational studies, the true incidence and impact of COVID-19 in the 'at-risk' population of patients with cancer is yet to be defined. METHODS: Epidemiological and clinical data were collected prospectively for patients attending the Royal Marsden Hospital and three network hospitals between March 1st and April 30th 2020 that were confirmed to have Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection. Significance of clinical and pathological characteristics was assessed using the Fisher's exact test and Wilcoxon rank sum test, whilst univariate and multivariate logistic regression models were used to further assess risk. The number of patients attending in March/April 2020 for face-to-face attendances was also extracted. FINDINGS: During the 2-month study period, 867 of 13,489 (6.4%) patients met the criteria leading to swab testing. Of the total at-risk population, only 113 of 13,489 (0.84%) were swab positive, 101 of 13,489 (0.75%) required hospital admission and 29 of 13,489 (0.21%) died of COVID-19. Of the patients that attended the hospital to receive cytotoxic chemotherapy alone or in combination with other therapy, 59 of 2001 (2.9%) were admitted to the hospital for COVID-19-related issues and 20 of 2001 (1%) died. Of the patients that collected targeted treatments, 16 of 1126 (1.4%) were admitted and 1 of 1126 (0.1%) died. Of the 11 patients that had received radiotherapy, 6 of 1042 (0.6%) required inpatient admission and 2 of 1042 (0.2%) died. INTERPRETATIONS: Administration of systemic anticancer therapy appears to be associated with a modest risk of severe COVID-19 infection. Based on this snapshot taken as the first wave of COVID-19 hit our practice, we conclude that continuation of active cancer treatment, even in the palliative setting, is appropriate.


Assuntos
Antineoplásicos/uso terapêutico , Infecções por Coronavirus/epidemiologia , Hospitalização/estatística & dados numéricos , Neoplasias/epidemiologia , Pneumonia Viral/epidemiologia , Radioterapia/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/mortalidade , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Feminino , Humanos , Incidência , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Mortalidade , Análise Multivariada , Neoplasias/terapia , Pandemias , Pneumonia Viral/mortalidade , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Fatores de Risco , Reino Unido/epidemiologia , Adulto Jovem
3.
Cancer Sci ; 111(9): 3313-3326, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32619077

RESUMO

The ongoing, Phase Ib MONALEESASIA study is evaluating the efficacy and safety of ribociclib plus endocrine therapy in Asian patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Eligible patients from Japan, Hong Kong, and Singapore were enrolled in this 2-phase study consisting of a dose-escalation phase to determine the maximum-tolerated dose and the recommended Phase II dose of ribociclib plus letrozole, and a dose-expansion phase to evaluate safety and tolerability of ribociclib plus letrozole, fulvestrant, or tamoxifen. An exploratory biomarker analysis evaluating expression of target genes was also conducted. In the dose-escalation phase, the maximum-tolerated/recommended Phase II doses of ribociclib were lower in Japanese patients (300 mg) than in Asian non-Japanese patients (600 mg). Ribociclib plus endocrine therapy at the recommended Phase II dose had a manageable safety profile, with neutropenia and elevated liver transaminases being the most common adverse events leading to dose modifications or discontinuations, and it demonstrated evidence of clinical activity in both Japanese and Asian non-Japanese patients. Preliminary efficacy in Asian populations is similar to that observed in White populations studied in previous ribociclib (MONALEESA) trials. Biomarker analysis demonstrated suppression of pharmacodynamic biomarker gene expression, indicating inhibition of target genes by ribociclib combined with endocrine therapy. Results from the ongoing study support the use of ribociclib in combination with letrozole in Asian non-Japanese patients at the same dose (600 mg) as White patients. In Japanese patients, a lower dose of ribociclib (300 mg) should be considered. Clinicaltrials.gov: NCT02333370.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Idoso , Idoso de 80 Anos ou mais , Aminopiridinas/administração & dosagem , Antineoplásicos Hormonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Grupo com Ancestrais do Continente Asiático , Biomarcadores , Neoplasias da Mama/etiologia , Neoplasias da Mama/mortalidade , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Feminino , Humanos , Japão , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/administração & dosagem , Purinas/administração & dosagem , Resultado do Tratamento
4.
Adv Cancer Res ; 148: 147-169, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32723562

RESUMO

The mammalian cell cycle is driven by a complex of cyclins and their associated cyclin-dependent kinases (CDKs). Abnormal dysregulation of cyclin-CDK is a hallmark of cancer. D-type cyclins and their associated CDKs (CDK4 and CDK6) are key components of cell cycle machinery in driving G1 to S phase transition via phosphorylating and inactivating the retinoblastoma protein (RB). A body of evidence shows that the cyclin Ds-CDKs axis plays a critical role in cancer through various aspects, such as control of proliferation, senescence, migration, apoptosis, and angiogenesis. CDK4/6 dual-inhibitors show significant efficacy in pre-clinical or clinical cancer therapies either as single agents or in combination with hormone, chemotherapy, irradiation or immune treatments. Of note, as the associated partner of D-type cyclins, CDK6 shows multiple distinct functions from CDK4 in cancer. Depletion of the individual CDK may provide a therapeutic strategy for patients with cancer.


Assuntos
Ciclina D/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Ciclina D/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Humanos , Neoplasias/enzimologia , Fosforilação , Inibidores de Proteínas Quinases/farmacologia
5.
PLoS One ; 15(6): e0233571, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32497134

RESUMO

PURPOSE: This meta-analysis aimed to assess the efficacy and safety of cyclin-dependent kinase (CDK) 4/6 inhibitors plus endocrine therapy (ET) in hormonal receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). METHODS: We searched PubMed, Embase, Cochrane, ClinicalTrials.gov., ASCO, ESMO and AACR databases from inception to October 10, 2019 for randomized controlled trials (RCTs) that compared CDK 4/6 inhibitors plus ET to single-agent ET with no treatment-line restriction. The main outcomes analyzed were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), and adverse events (AEs). RESULTS: Of 938 identified studies, 9 RCTs with 5043 women were eligible and included. Compared with ET alone, CDK 4/6 inhibitors and ET combination improved in PFS (hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.50-0.59, p< 0.00001) and OS (HR 0.77, 95% CI 0.69-0.85, p< 0.00001), regardless of ET strategies (HR 0.54, 95% CI 0.50-0.59 in PFS; HR 0.77, 95% CI 0.69-0.85 in OS), treatment line of advanced disease (HR 0.52, 95% CI 0.46-0.59 in PFS; HR 0.75, 95% CI 0.66-0.85 in OS) and menopausal status (HR 0.54, 95% CI 0.50-0.58 in PFS; HR 0.76, 95% CI 0.68-0.84 in OS). Higher risk of grade 3/4 AEs (RR 2.66, 95% CI 2.44-2.90, p < 0.00001) were observed in the combination group than in the ET group. CONCLUSIONS: Combination therapy with CDK 4/6 inhibitors and ET prolongs survival in HR+/ HER2- ABC. This combination is a better therapeutic strategy than endocrine monotherapy in HR+/HER2- ABC, regardless of treatment line, menopausal status and other individual characteristics.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos
6.
Toxicol Appl Pharmacol ; 401: 115109, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32544403

RESUMO

Bladder cancer (BCa) is the fourth leading cause of cancer deaths worldwide due to its aggressiveness and resistance against therapies. Intricate interactions between cancer cells and the tumor microenvironment (TME) are essential for both disease progression and regression. Thus, interrupting molecular communications within the TME could potentially provide improved therapeutic efficacies. M2-polarized tumor-associated macrophages (M2 TAMs) were shown to contribute to BCa progression and drug resistance. We attempted to provide evidence for ovatodiolide (OV) as a potential therapeutic agent that targets both TME and BCa cells. First, tumor-suppressing functions of OV were determined by cell viability, colony, and tumor-sphere formation assays using a coculture system composed of M2 TAMs/BCa cells. Subsequently, we demonstrated that extracellular vesicles (EVs) isolated from M2 TAMs containing oncomiR-21 and mRNAs, including Akt, STAT3, mTOR, and ß-catenin, promoted cisplatin (CDDP) resistance, migration, and tumor-sphere generation in BCa cells, through increasing CDK6, mTOR, STAT3, and ß-catenin expression. OV treatment also prevented M2 polarization and reduced EV cargos from M2 TAMs. Finally, in vivo data demonstrated that OV treatment overcame CDDP resistance. OV only and the OV + CDDP combination both resulted in significant reductions in mTOR, ß-catenin, CDK6, and miR-21 expression in tumor samples and EVs isolated from serum. Collectively, we demonstrated that M2 TAMs induced malignant properties in BCa cells, in part via oncogenic EVs. OV treatment prevented M2 TAM polarization, reduced EV cargos derived from M2 TAMs, and suppressed ß-catenin/mTOR/CDK6 signaling. These findings provide preclinical evidence for OV as a single or adjuvant agent for treating drug-resistant BCa.


Assuntos
Quinase 6 Dependente de Ciclina/metabolismo , Diterpenos/uso terapêutico , MicroRNAs/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , beta Catenina/metabolismo , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Técnicas de Cocultura , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Relação Dose-Resposta a Droga , Exossomos/efeitos dos fármacos , Exossomos/metabolismo , Exossomos/patologia , Feminino , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , MicroRNAs/antagonistas & inibidores , Plantas Medicinais , Serina-Treonina Quinases TOR/antagonistas & inibidores , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , beta Catenina/antagonistas & inibidores
7.
Nat Commun ; 11(1): 2350, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32393766

RESUMO

BET inhibitors are promising therapeutic agents for the treatment of triple-negative breast cancer (TNBC), but the rapid emergence of resistance necessitates investigation of combination therapies and their effects on tumor evolution. Here, we show that palbociclib, a CDK4/6 inhibitor, and paclitaxel, a microtubule inhibitor, synergize with the BET inhibitor JQ1 in TNBC lines. High-complexity DNA barcoding and mathematical modeling indicate a high rate of de novo acquired resistance to these drugs relative to pre-existing resistance. We demonstrate that the combination of JQ1 and palbociclib induces cell division errors, which can increase the chance of developing aneuploidy. Characterizing acquired resistance to combination treatment at a single cell level shows heterogeneous mechanisms including activation of G1-S and senescence pathways. Our results establish a rationale for further investigation of combined BET and CDK4/6 inhibition in TNBC and suggest novel mechanisms of action for these drugs and new vulnerabilities in cells after emergence of resistance.


Assuntos
Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos , Proteínas/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Azepinas/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Clonais , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , DNA de Neoplasias/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Camundongos , Modelos Biológicos , Mutação/genética , Paclitaxel/farmacologia , Piperazinas/farmacologia , Ploidias , Proteínas/metabolismo , Piridinas/farmacologia , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo , Resultado do Tratamento , Triazóis/farmacologia , Neoplasias de Mama Triplo Negativas/genética , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
8.
Lancet ; 395(10226): 817-827, 2020 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-32145796

RESUMO

The development and approval of cyclin-dependent kinase (CDK) 4 and 6 inhibitors for hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer represents a major milestone in cancer therapeutics. Three different oral CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, have significantly improved progression-free survival by a number of months when combined with endocrine therapy. More recently, improvement in overall survival has been reported with ribociclib and abemaciclib. The toxicity profile of all three drugs is well described and generally easily manageable with dose reductions when indicated. More myelotoxicity is observed with palbociclib and ribociclib, but more gastrointestinal toxicity is observed with abemaciclib. Emerging data is shedding light on the resistance mechanisms associated with CDK4/6 inhibitors, including cell cycle alterations and activation of upstream tyrosine kinase receptors. A number of clinical trials are exploring several important questions regarding treatment sequencing, combinatorial strategies, and the use of CDK4/6 inhibitors in the adjuvant and neoadjuvant settings, thereby further expanding and refining the clinical application of CDK4/6 inhibitors for patients with breast cancer.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Ciclo Celular/efeitos dos fármacos , Ensaios Clínicos como Assunto , Feminino , Previsões , Humanos , Receptores Estrogênicos , Receptores de Progesterona
9.
J Med Chem ; 63(6): 3327-3347, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32129996

RESUMO

Cyclin-dependent kinases (CDKs) are promising therapeutic targets for cancer therapy. Herein, we describe our efforts toward the discovery of a series of 5-chloro-N4-phenyl-N2-(pyridin-2-yl)pyrimidine-2,4-diamine derivatives as dual CDK6 and 9 inhibitors. Intensive structural modifications lead to the identification of compound 66 as the most active dual CDK6/9 inhibitor with balancing potency against these two targets and good selectivity over CDK2. Further biological studies revealed that compound 66 was directly bound to CDK6/9, resulting in suppression of their downstream signaling pathway and inhibition of cell proliferation by blocking cell cycle progression and inducing cellular apoptosis. More importantly, compound 66 significantly inhibited tumor growth in a xenograft mouse model with no obvious toxicity, indicating the promising therapeutic potential of CDK6/9 dual inhibitors for cancer treatment. Therefore, the above results are of great importance in the development of dual CDK6/9 inhibitors for cancer therapy.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/química , Quinase 6 Dependente de Ciclina/metabolismo , Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Quinase 9 Dependente de Ciclina/química , Quinase 9 Dependente de Ciclina/metabolismo , Humanos , Masculino , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Piridinas/administração & dosagem , Piridinas/síntese química , Piridinas/metabolismo , Pirimidinas/administração & dosagem , Pirimidinas/síntese química , Pirimidinas/metabolismo , Ratos Sprague-Dawley , Relação Estrutura-Atividade
10.
Cancer Sci ; 111(5): 1761-1773, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32103527

RESUMO

The cyclin-dependent kinase (CDK)4/6-cyclin D1-Rb-p16/ink4a pathway is responsible for regulating cell progression past the G1 restriction point during the cell cycle. The development of a majority of human tumors is associated with dysregulation of this pathway, resulting in increased cancer cell proliferation. Both CDK4 and CDK6, well-validated cancer drug targets, function primarily as catalytic enzymes that mediate the phosphorylation of retinoblastoma protein (Rb). Here, we determined that SPH3643 is a novel potent antiproliferative agent that inhibits CDK4/6 kinase activity. In biochemical assays, SPH3643 showed more potent inhibition of both CDK4 and CDK6 than did 2 published CDK4/6 inhibitors, LY2835219 and palbociclib, and had better selectivity than LY2835219. Further in vitro study revealed that SPH3643 blocked Cdk/Rb signaling by inhibiting the phosphorylation of RbSer780 and arrested the MCF-7 cancer cells at G0 /G1 phase, resulting in marked inhibition of the proliferation of Rb-positive cancer cell lines. In vivo SPH3643 treatment in mice bearing xenograft tumor models of breast cancer, colon cancer, acute myelocytic leukemia, and glioblastoma resulted in significant decreases in tumor growth. SPH3643 was able to particularly strongly inhibit glioblastoma (U87-MG) cell growth in the brains of orthotopic carcinoma xenograft mice due to its high degree of intracerebral penetration and significant persistence in this setting. Together these results revealed that SPH3643 is a potent, orally active small-molecule inhibitor of CDK4/6 with robust anticancer efficacy and a high degree of blood-brain barrier permeability.


Assuntos
Antineoplásicos/farmacologia , Barreira Hematoencefálica/metabolismo , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Animais , Antineoplásicos/uso terapêutico , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Nus , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Proteína do Retinoblastoma/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Cancer Cell ; 37(3): 340-353.e6, 2020 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-32109375

RESUMO

Inhibition of the cell-cycle kinases CDK4 and CDK6 is now part of the standard treatment in advanced breast cancer. CDK4/6 inhibitors, however, are not expected to cooperate with DNA-damaging or antimitotic chemotherapies as the former prevent cell-cycle entry, thus interfering with S-phase- or mitosis-targeting agents. Here, we report that sequential administration of CDK4/6 inhibitors after taxanes cooperates to prevent cellular proliferation in pancreatic ductal adenocarcinoma (PDAC) cells, patient-derived xenografts, and genetically engineered mice with Kras G12V and Cdkn2a-null mutations frequently observed in PDAC. This effect correlates with the repressive activity of CDK4/6 inhibitors on homologous recombination proteins required for the recovery from chromosomal damage. CDK4/6 inhibitors also prevent recovery from multiple DNA-damaging agents, suggesting broad applicability for their sequential administration after available chemotherapeutic agents.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Neoplasias Pancreáticas/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Albuminas/administração & dosagem , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Inibidor p16 de Quinase Dependente de Ciclina/genética , Reparo do DNA/efeitos dos fármacos , Esquema de Medicação , Recombinação Homóloga/efeitos dos fármacos , Humanos , Camundongos Nus , Camundongos Transgênicos , Mutação , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/genética , Paclitaxel/administração & dosagem , Neoplasias Pancreáticas/patologia , Piperazinas/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/genética , Piridinas/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Cancer Res ; 80(4): 757-770, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31843982

RESUMO

Aberrant Notch and Wnt signaling are known drivers of cholangiocarcinoma (CCA), but the underlying factors that initiate and maintain these pathways are not known. Here, we show that the proline-rich homeodomain protein/hematopoietically expressed homeobox (PRH/HHEX) transcription factor forms a positive transcriptional feedback loop with Notch3 that is critical in CCA. PRH/HHEX expression is elevated in CCA, and depletion of PRH reduces CCA tumor growth in a xenograft model. Overexpression of PRH in primary human biliary epithelial cells is sufficient to increase cell proliferation and produce an invasive phenotype. Interrogation of the gene networks regulated by PRH and Notch3 reveals that unlike Notch3, PRH directly activates canonical Wnt signaling. These data indicate that hyperactivation of Notch and Wnt signaling is independent of the underlying mutational landscape and has a common origin in dysregulation of PRH. Moreover, they suggest new therapeutic options based on the dependence of specific Wnt, Notch, and CDK4/6 inhibitors on PRH activity. SIGNIFICANCE: The PRH/HHEX transcription factor is an oncogenic driver in cholangiocarcinoma that confers sensitivity to CDK4/6 inhibitors.


Assuntos
Antineoplásicos/farmacologia , Neoplasias dos Ductos Biliares/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Proteínas de Homeodomínio/metabolismo , Receptor Notch3/metabolismo , Fatores de Transcrição/metabolismo , Animais , Antineoplásicos/uso terapêutico , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/citologia , Ductos Biliares Intra-Hepáticos/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/genética , Células Epiteliais , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Redes Reguladoras de Genes , Proteínas de Homeodomínio/genética , Humanos , Células K562 , Masculino , Camundongos , Mutação , Invasividade Neoplásica/genética , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Cultura Primária de Células , Regiões Promotoras Genéticas , Piridinas/farmacologia , Piridinas/uso terapêutico , RNA-Seq , Fatores de Transcrição/genética , Via de Sinalização Wnt/genética , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Lancet Oncol ; 21(2): 250-260, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31859246

RESUMO

BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors (CDKIs) are indicated with endocrine therapy as first-line or second-line treatment for hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer. We aimed to investigate the benefit of adding CDKIs to endocrine therapy in patients whose tumours might have differing degrees of endocrine sensitivity. METHODS: We pooled individual patient data from all phase 3 randomised breast cancer trials of CDKIs plus endocrine therapy submitted to the US Food and Drug Administration before Jan 1, 2019, in support of marketing applications. Our pooled analysis included all randomly assigned patients in these trials who received at least one dose of CDKI or placebo with endocrine therapy (an aromatase inhibitor [letrozole or anastrazole] or fulvestrant). We did prespecified subgroup analyses in patients with progesterone receptor-negative disease; patients with a disease-free interval of 12 months or less; patients with de-novo metastases, lobular histology, and bone-only disease; patients with visceral metastases; and patients aged up to 40 years. Patients who were not treated, who received tamoxifen as endocrine therapy, or who were treated with an aromatase inhibitor but who had received previous chemotherapy in the metastatic setting (not first-line) were excluded from our pooled analyses. All studies had a primary endpoint of investigator-assessed progression-free survival, defined as time from date of randomisation to the initial date of documented cancer progression or death, whichever occurred first. Median progression-free survival was estimated with Kaplan-Meier methods. Hazard ratios (HR) with 95% CIs for progression-free survival were estimated by means of Cox regression models. FINDINGS: The seven studies meeting this study's inclusion criteria were done between Feb 22, 2013, and Nov 3, 2017, with a median duration of follow-up of 19·7 months (IQR 15·9-25·9). 4200 patients were included in the pooled analysis, of whom 1320 received an aromatase inhibitor plus a CDKI, 932 received placebo plus an aromatase inhibitor, 1296 received fulvestrant plus a CDKI, and 652 received fulvestrant plus placebo. Across all seven pooled trials, the difference in estimated median progression-free survival was 8·8 months in favour of CDKI plus endocrine therapy over placebo plus endocrine therapy (range across the trials 6·8-13·3 months; HR 0·59, 95% CI 0·54-0·64). Progression-free survival results favoured the CDKI group in all prespecified clinicopathological subgroups analysed, with similar HRs to that for the broader intended-use population. In first-line aromatase inhibitor-treated patients (n=2252), the median progression-free survival in the CDKI plus aromatase inhibitor group was 28·0 months (95% CI 25·3-29·1) versus 14·9 months (14·0-16·7) in the placebo plus aromatase inhibitor group (difference 13·1 months; range across the trials 13·0-13·3 months; HR 0·55, 95% CI 0·49-0·62). In first-line fulvestrant-treated patients (n=396), the median progression-free survival was 18·6 months (95% CI 14·8-23·5) in the placebo plus fulvestrant group and not estimable (22·4 to not estimable) in the CDKI plus fulvestrant group (difference not estimable; HR 0·58, 95% CI 0·42-0·80). In the patients treated with fulvestrant in the second-line setting and beyond (n=1552), the difference in estimated median progression-free survival between the CDKI plus fulvestrant group and the placebo plus fulvestrant group was 6·9 months in favour of the CDKI group (range across the trials 5·5-7·3 months; HR 0·56, 95% CI 0·49-0·64). INTERPRETATION: Since the addition of CDKI to endocrine therapy seemed to benefit all clinicopathological subgroups of interest in this pooled analysis, further research is needed to identify patient subgroups for whom endocrine therapy alone might be appropriate for first-line or second-line treatment of hormone receptor-positive, HER2-negative metastatic breast cancer. FUNDING: None.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Inibidores da Aromatase/administração & dosagem , Biomarcadores Tumorais/análise , Neoplasias da Mama/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/administração & dosagem , Receptor ErbB-2/análise , Receptores Estrogênicos/análise , Receptores de Progesterona/análise , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Ensaios Clínicos Fase III como Assunto , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Aprovação de Drogas , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Transdução de Sinais , Fatores de Tempo , Estados Unidos , United States Food and Drug Administration
14.
Cancer Res ; 80(5): 1064-1077, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31862778

RESUMO

miR-223 is an anti-inflammatory miRNA that in cancer acts either as an oncosuppressor or oncopromoter, in a context-dependent manner. In breast cancer, we demonstrated that it dampens the activation of the EGF pathway. However, little is known on the role of miR-223 during breast cancer onset and progression. miR-223 expression was decreased in breast cancer of luminal and HER2 subtypes and inversely correlated with patients' prognosis. In normal luminal mammary epithelial cells, miR-223 acted cell autonomously in the control of their growth and morphology in three-dimensional context. In the MMTV-Δ16HER2 transgenic mouse model, oncogene transformation resulted in a timely abrogation of miR-223 expression, likely due to activation of E2F1, a known repressor of miR-223 transcription. Accordingly, treatment with CDK4/6 inhibitors, which eventually results in restraining E2F1 activity, restored miR-223 expression and miR-223 ablation induced luminal breast cancer resistance to CDK4/6 inhibition, both in vitro and in vivo. Notably, miR-223 expression was lost in microdissected ductal carcinoma in situ (DCIS) from patients with luminal and HER2-positive breast cancer. Altogether, these results identify downmodulation of miR-223 as an early step in luminal breast cancer onset and suggest that it could be used to identify aggressive DCIS and predict the response to targeted therapy. SIGNIFICANCE: miR-223 may represent a predictive biomarker of response to CDK4/6 inhibitors and its loss could identify DCIS lesions that are likely to progress into invasive breast cancer.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/genética , Carcinoma Intraductal não Infiltrante/genética , Transformação Celular Neoplásica/genética , MicroRNAs/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antineoplásicos/uso terapêutico , Mama/citologia , Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/tratamento farmacológico , Carcinoma Intraductal não Infiltrante/mortalidade , Carcinoma Intraductal não Infiltrante/patologia , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Modelos Animais de Doenças , Progressão da Doença , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos/genética , Fator de Transcrição E2F1/metabolismo , Células Epiteliais , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/patologia , Camundongos Knockout , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Prognóstico , Piridinas/farmacologia , Piridinas/uso terapêutico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo
15.
Breast Cancer Res ; 21(1): 146, 2019 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-31852484

RESUMO

BACKGROUND: Addition of CDK4/6 inhibitors (CDK4/6i) to endocrine therapy significantly increased progression-free survival, leading to their approval and incorporation into the metastatic breast cancer treatment paradigm. With these inhibitors being routinely used for patients with advanced estrogen receptor-positive (ER+) breast cancer, resistance to these agents and its impact on subsequent therapy needs to be understood. Considering the central role of ER in driving the growth of ER+ breast cancers, and thus endocrine agents being a mainstay in the treatment paradigm, the effects of prior CDK4/6i exposure on ER signaling and the relevance of ER-targeted therapy are important to investigate. The objective of this study was to evaluate the anti-tumor activity of elacestrant, a novel oral selective estrogen receptor degrader (SERD), in preclinical models of CDK4/6i resistance. METHODS: Elacestrant was evaluated as a single agent, and in combination with alpelisib or everolimus, in multiple in vitro models and patient-derived xenografts that represent acquired and "de novo" CDK4/6i resistance. RESULTS: Elacestrant demonstrated growth inhibition in cells resistant to all three approved CDK4/6i (palbociclib, abemaciclib, ribociclib) in both ESR1 wild-type and mutant backgrounds. Furthermore, we demonstrated that elacestrant, as a single agent and in combination, inhibited growth of patient-derived xenografts that have been derived from a patient previously treated with a CDK4/6i or exhibit de novo resistance to CDK4/6i. While the resistant lines demonstrate distinct alterations in cell cycle modulators, this did not affect elacestrant's anti-tumor activity. In fact, we observe that elacestrant downregulates several key cell cycle players and halts cell cycle progression in vitro and in vivo. CONCLUSIONS: We demonstrate that breast cancer tumor cells continue to rely on ER signaling to drive tumor growth despite exposure to CDK4/6i inhibitors. Importantly, elacestrant can inhibit this ER-dependent growth despite previously reported mechanisms of CDK4/6i resistance observed such as Rb loss, CDK6 overexpression, upregulated cyclinE1 and E2F1, among others. These data provide a scientific rationale for the evaluation of elacestrant in a post-CDK4/6i patient population. Additionally, elacestrant may also serve as an endocrine backbone for rational combinations to combat resistance.


Assuntos
Neoplasias da Mama/metabolismo , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos , Inibidores de Proteínas Quinases/farmacologia , Receptores Estrogênicos/metabolismo , Tetra-Hidronaftalenos/farmacologia , Animais , Antineoplásicos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Modelos Biológicos , Terapia de Alvo Molecular , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Curr Drug Res Rev ; 11(2): 135-141, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31875784

RESUMO

BACKGROUND: Cyclin-Dependent Kinases-6 (CDK-6) is a serine/threonine protein kinase with regular activity in the cell cycle. Some inhibitors, such as abemaciclib, hymenialdisine, and indirubin, cause cell arrest by decreasing its activity. OBJECTIVES: The purpose of this study was to evaluate the Molecular Dynamic (MD) effects of abemaciclib, hymenialdisine, and indirubin on the structure of CDK-6. METHODS: The PDB file of CDK-6 was obtained from the Protein Data Bank (http://www.rcsb.org). After the simulation of CDK-6 in the Gromacs software, 200 stages of molecular docking were run on CDK-6 in the presence of the inhibitors using AutoDock 4.2. The simulation of CDK-6 in the presence of inhibitors was performed after docking. RESULTS: Abemaciclib showed the greatest tendency to bind CDK-6 via binding 16 residues in the binding site with hydrogen bonds and hydrophobic bonding. CDK-6 docked to hymenialdisine and indirubin increased the Total Energy (TE) and decreased the radius of gyration (Rg). CDK-6 docked to hymenialdisine significantly decreased the coil secondary structure. CONCLUSION: CDK-6 is inhibited via high binding affinity to abemaciclib, hymenialdisine, and indirubin inhibitors and induces variation in the secondary structure and Rg in the CDK-6 docked to the three inhibitors. It seems that developing a drug with a binding tendency to CDK6 that is similar to those of abemaciclib, indirubin, and hymenialdisine can change the secondary structure of CDK6, possibly more potently, and can be used to develop anticancer drugs. However, additional studies are needed to confirm this argument.


Assuntos
Aminopiridinas/farmacologia , Antineoplásicos/farmacologia , Azepinas/farmacologia , Benzimidazóis/farmacologia , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirróis/farmacologia , Sítios de Ligação/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Simulação por Computador , Humanos , Ligação de Hidrogênio , Indóis/farmacologia , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular
17.
Breast Cancer Res ; 21(1): 150, 2019 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-31878959

RESUMO

BACKGROUND: CDK4/6 inhibitors in combination with endocrine therapy (AE/AI/SERDs) are approved for the treatment of ER+ advanced breast cancer (BCa). However, not all patients benefit from CDK4/6 inhibitors therapy. We previously reported a novel therapeutic agent, ERX-11, that binds to the estrogen receptor (ER) and modulates ER-coregulator interactions. Here, we tested if the combination of ERX-11 with agents approved for ER+ BCa would be more potent. METHODS: We tested the effect of combination therapy using BCa cell line models, including those that have acquired resistance to tamoxifen, letrozole, or CDK4/6 inhibitors or have been engineered to express mutant forms of the ER. In vitro activity was tested using Cell Titer-Glo, MTT, and apoptosis assays. Mechanistic studies were conducted using western blot, reporter gene assays, RT-qPCR, and mass spectrometry approaches. Xenograft, patient-derived explants (PDEs), and xenograft-derived explants (XDE) were used for preclinical evaluation and toxicity. RESULTS: ERX-11 inhibited the proliferation of therapy-resistant BCa cells in a dose-dependent manner, including ribociclib resistance. The combination of ERX-11 and CDK4/6 inhibitor was synergistic in decreasing the proliferation of both endocrine therapy-sensitive and endocrine therapy-resistant BCa cells, in vitro, in xenograft models in vivo, xenograft-derived explants ex vivo, and in primary patient-derived explants ex vivo. Importantly, the combination caused xenograft tumor regression in vivo. Unbiased global mass spectrometry studies demonstrated profound decreases in proliferation markers with combination therapy and indicated global proteomic changes in E2F1, ER, and ER coregulators. Mechanistically, the combination of ERX-11 and CDK4/6 inhibitor decreased the interaction between ER and its coregulators, as evidenced by immunoprecipitation followed by mass spectrometry studies. Biochemical studies confirmed that the combination therapy significantly altered the expression of proteins involved in E2F1 and ER signaling, and this is primarily driven by a transcriptional shift, as noted in gene expression studies. CONCLUSIONS: Our results suggest that ERX-11 inhibited the proliferation of BCa cells resistant to both endocrine therapy and CDK4/6 inhibitors in a dose-dependent manner and that the combination of ERX-11 with a CDK4/6 inhibitor may represent a viable therapeutic approach.


Assuntos
Biomarcadores Tumorais , Neoplasias da Mama/metabolismo , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Moduladores de Receptor Estrogênico/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Receptores Estrogênicos/metabolismo , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Feminino , Humanos , Imuno-Histoquímica , Camundongos
18.
EBioMedicine ; 50: 111-121, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31761618

RESUMO

PURPOSE: Ponatinib is the only approved tyrosine kinase inhibitor (TKI) suppressing BCR-ABL1T315I-mutated cells in chronic myeloid leukemia (CML). However, due to side effects and resistance, BCR-ABL1T315I-mutated CML remains a clinical challenge. Hydroxyurea (HU) has been used for cytoreduction in CML for decades. We found that HU suppresses or even eliminates BCR-ABL1T315I+ sub-clones in heavily pretreated CML patients. Based on this observation, we investigated the effects of HU on TKI-resistant CML cells in vitro. METHODS: Viability, apoptosis and proliferation of drug-exposed primary CML cells and BCR-ABL1+ cell lines were examined by flow cytometry and 3H-thymidine-uptake. Expression of drug targets was analyzed by qPCR and Western blotting. FINDINGS: HU was more effective in inhibiting the proliferation of leukemic cells harboring BCR-ABL1T315I or T315I-including compound-mutations compared to cells expressing wildtype BCR-ABL1. Moreover, HU synergized with ponatinib and ABL001 in inducing growth inhibition in CML cells. Furthermore, HU blocked cell cycle progression in leukemic cells, which was accompanied by decreased expression of CDK4 and CDK6. Palbociclib, a more specific CDK4/CDK6-inhibitor, was also found to suppress proliferation in primary CML cells and to synergize with ponatinib in producing growth inhibition in BCR-ABL1T315I+ cells, suggesting that suppression of CDK4/CDK6 may be a promising concept to overcome BCR-ABL1T315I-associated TKI resistance. INTERPRETATION: HU and the CDK4/CDK6-blocker palbociclib inhibit growth of CML clones expressing BCR-ABL1T315I or complex T315I-including compound-mutations. Clinical studies are required to confirm single drug effects and the efficacy of `ponatinib+HU´ and ´ponatinib+palbociclib´ combinations in advanced CML. FUNDING: This project was supported by the Austrian Science Funds (FWF) projects F4701-B20, F4704-B20 and P30625.


Assuntos
Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Mutação , Inibidores de Proteínas Quinases/farmacologia , Adulto , Idoso , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Feminino , Humanos , Hidroxiureia/farmacologia , Hidroxiureia/uso terapêutico , Imidazóis/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/uso terapêutico , Piridazinas/farmacologia
20.
Nat Commun ; 10(1): 5076, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31700061

RESUMO

Previous studies from the Cancer Cell Line Encyclopedia (CCLE) project have adopted commercial pan-cancer cell line models to identify drug sensitivity biomarkers. However, drug sensitivity biomarkers in esophageal squamous cell carcinoma (ESCC) have not been widely explored. Here, eight patient-derived cell lines (PDCs) are successfully established from 123 patients with ESCC. The mutation profiling of PDCs can partially recapture the tumor tissue actionable mutations from 161 patients with ESCC. Based on these mutations and relative pathways in eight PDCs, 46 targeted drugs are selected for screening. Interestingly, some drug and biomarker relationships are established that were not discovered in the CCLE project. For example, CDKN2A or CDKN2B loss is significantly associated with the sensitivity of CDK4/6 inhibitors. Furthermore, both PDC xenografts and patient-derived xenografts confirm CDKN2A/2B loss as a biomarker predictive of CDK4/6 inhibitor sensitivity. Collectively, patient-derived models could predict targeted drug sensitivity associated with actionable mutations in ESCC.


Assuntos
Aminopiridinas/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Purinas/uso terapêutico , Piridinas/uso terapêutico , Adulto , Idoso , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Resistencia a Medicamentos Antineoplásicos , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Ensaios Antitumorais Modelo de Xenoenxerto
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