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1.
Anticancer Res ; 41(10): 4807-4820, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34593430

RESUMO

BACKGROUND/AIM: LY2835219 (LY), a novel CDK4/6 inhibitor, prevents cell proliferation through G1 arrest. Docetaxel (DTX) and paclitaxel (PTX) are cytotoxic drugs targeting tubulin-mediated apoptotic cell death via G2/M arrest. We evaluated the antitumor effects of DTX/PTX and LY individually and in combination in lung adenocarcinoma cells with or without KRAS mutations and xenograft mice harboring KRAS mutations. MATERIALS AND METHODS: We investigated in vitro/in vivo changes in signaling molecules and analyzed cell proliferation, cycle, and apoptosis via flow cytometry and western blotting. RESULTS: LY cytotoxicity was dose-dependent and varied with KRAS mutation status. DTX→LY showed synergistic cytotoxicity regardless of KRAS mutation. Furthermore, the synergistic effect of PTX→LY was significantly greater than that of PTX+LY. DTX→LY remarkably reduced the number of G0/G1 cells and increased the number of G2/M arrested cells, resulting in an increase in apoptosis and subG1 cells. CONCLUSION: DTX→LY has synergistic antitumor effect in lung cancer cells and xenograft mice regardless of KRAS mutation.


Assuntos
Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Proto-Oncogênicas p21(ras)/genética , Taxoides/farmacologia , Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Mutação , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Transdução de Sinais/efeitos dos fármacos , Taxoides/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Nat Commun ; 12(1): 5386, 2021 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-34508104

RESUMO

Although inhibitors targeting CDK4/6 kinases (CDK4/6i) have shown promising clinical prospect in treating ER+/HER2- breast cancers, acquired drug resistance is frequently observed and mechanistic knowledge is needed to harness their full clinical potential. Here, we report that inhibition of CDK4/6 promotes ßTrCP1-mediated ubiquitination and proteasomal degradation of RB1, and facilitates SP1-mediated CDK6 transcriptional activation. Intriguingly, suppression of CK1ε not only efficiently prevents RB1 from degradation, but also prevents CDK4/6i-induced CDK6 upregulation by modulating SP1 protein stability, thereby enhancing CDK4/6i efficacy and overcoming resistance to CDK4/6i in vitro. Using xenograft and PDX models, we further demonstrate that combined inhibition of CK1ε and CDK4/6 results in marked suppression of tumor growth in vivo. Altogether, these results uncover the molecular mechanisms by which CDK4/6i treatment alters RB1 and CDK6 protein abundance, thereby driving the acquisition of CDK4/6i resistance. Importantly, we identify CK1ε as an effective target for potentiating the therapeutic efficacy of CDK4/6 inhibitors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Caseína Quinase Iépsilon/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Inibidores de Proteínas Quinases/uso terapêutico , Estabilidade Proteica/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Proteínas de Ligação a Retinoblastoma/metabolismo , Fator de Transcrição Sp1/metabolismo , Ativação Transcricional/efeitos dos fármacos , Ubiquitina-Proteína Ligases/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Int J Mol Sci ; 22(16)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34445095

RESUMO

The expanding clinical application of CDK4- and CDK6-inhibiting drugs in the managements of breast cancer has raised a great interest in testing these drugs in other neoplasms. The potential of combining these drugs with other therapeutic approaches seems to be an interesting work-ground to explore. Even though a potential integration of CDK4 and CDK6 inhibitors with radiotherapy (RT) has been hypothesized, this kind of approach has not been sufficiently pursued, neither in preclinical nor in clinical studies. Similarly, the most recent discoveries focusing on autophagy, as a possible target pathway able to enhance the antitumor efficacy of CDK4 and CDK6 inhibitors is promising but needs more investigations. The aim of this review is to discuss the recent literature on the field in order to infer a rational combination strategy including cyclin-D1/CDK4-CDK6 inhibitors, RT, and/or other anticancer agents targeting G1-S phase cell cycle transition.


Assuntos
Antineoplásicos/uso terapêutico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Autofagia/efeitos da radiação , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/efeitos da radiação , Quimiorradioterapia , Ciclina D1/antagonistas & inibidores , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Humanos , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacologia
4.
Nat Commun ; 12(1): 5112, 2021 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-34433817

RESUMO

CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy have shown impressive efficacy in estrogen receptor-positive advanced breast cancer. However, most patients will eventually experience disease progression on this combination, underscoring the need for effective subsequent treatments or better initial therapies. Here, we show that triple inhibition with fulvestrant, CDK4/6i and AKT inhibitor (AKTi) durably impairs growth of breast cancer cells, prevents progression and reduces metastasis of tumor xenografts resistant to CDK4/6i-fulvestrant combination or fulvestrant alone. Importantly, switching from combined fulvestrant and CDK4/6i upon resistance to dual combination with AKTi and fulvestrant does not prevent tumor progression. Furthermore, triple combination with AKTi significantly inhibits growth of patient-derived xenografts resistant to combined CDK4/6i and fulvestrant. Finally, high phospho-AKT levels in metastasis of breast cancer patients treated with a combination of CDK4/6i and endocrine therapy correlates with shorter progression-free survival. Our findings support the clinical development of ER, CDK4/6 and AKT co-targeting strategies following progression on CDK4/6i and endocrine therapy combination, and in tumors exhibiting high phospho-AKT levels, which are associated with worse clinical outcome.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Fulvestranto/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/genética , Quinase 6 Dependente de Ciclina/metabolismo , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Quimioterapia Combinada , Feminino , Humanos , Terapia de Alvo Molecular , Proteínas Proto-Oncogênicas c-akt/genética
5.
Curr Oncol ; 28(3): 2270-2280, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207443

RESUMO

In this analysis, we describe population-based outcomes for first-line treatment with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) combined with an aromatase inhibitor (AI). All patients who were prescribed CDK4/6i + AI from January 2016 through June 2019 were included. Patient demographics, tumour and treatment characteristics were collected and described. Survival distributions were estimated using the Kaplan-Meier method. Multivariate analysis (MVA) was constructed to examine associations between potentially prognostic clinical variables and progression-free survival (PFS). In total, 316 patients were included. The median age was 61 years. After a median follow-up of 28.1 months, the median PFS was 37.9 months (95% CI, 26.7-NR). In the MVA, PR-negative tumour (HR, 2.37; 95% CI, 1.45-3.88; p = 0.001) and CDK4/6i dose reduction (HR, 1.51; 95% CI, 1.06-2.16; p = 0.022) predicted worse PFS. Median overall survival (OS) was not reached. The 30-month and 36-month OS rates were 74% and 68%, respectively. Of patients who progressed, 89% received second-line treatment. Median time to progression on second-line chemotherapy was 9.0 (5.8-17.6) months, and median time to progression on second-line hormonal therapy +/- targeted agent was 4.0 (3.4-8.6) months (p = 0.012). CDK4/6i + AI as first-line treatment for HR-positive, HER2-negative MBC in Alberta is justified based on favourable PFS and early OS outcomes.


Assuntos
Inibidores da Aromatase , Neoplasias da Mama , Alberta , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Receptor ErbB-2
6.
BMJ Case Rep ; 14(7)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34312131

RESUMO

A 72-year-old woman with metastatic ER/PR-positive breast cancer who had been on ribociclib and letrozole for 1 year developed severe life-threatening colitis. She presented to emergency department with features of acute abdomen and diarrhoea. The diagnosis of colitis was confirmed radiologically as well as by histopathological examination of the biopsy specimen and the patient clinically improved after withholding ribociclib and receiving corticosteroids compatible with ribociclib-induced colitis. The mechanism of injury in CDK 4/6 inhibitor-induced colitis is unknown but may be related to recruitment of inflammatory cells. Whether the development of colitis is associated with tumour response is an interesting and unanswered question.


Assuntos
Aminopiridinas/efeitos adversos , Neoplasias da Mama , Colite , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Purinas/efeitos adversos , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama/tratamento farmacológico , Colite/induzido quimicamente , Feminino , Humanos , Letrozol/uso terapêutico , Receptor ErbB-2 , Receptores de Estrogênio
7.
Anticancer Res ; 41(7): 3287-3292, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230123

RESUMO

BACKGROUND: Osteosarcoma is the most frequent malignant bone neoplasm. The efficacy of combination therapy of a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor and a mammalian-target-of-rapamycin (mTOR) inhibitor was previously reported in several cancer types. In the present study, we evaluated the efficacy of a combination of palbociclib (CDK 4/6 inhibitor) and everolimus (mTOR inhibitor) on an osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model. MATERIALS AND METHODS: osteosarcoma PDOX mouse models were randomized into five treatment groups of seven mice each: Group 1, untreated control; group 2, doxorubicin treatment; group 3, palbociclib treatment; group 4, everolimus treatment; group 5, palbociclib-everolimus combination treatment. Treatment duration was 2 weeks. RESULTS: The palbociclib-everolimus combination reduced the tumor-volume ratio in the osteosarcoma PDOX mouse model compared with the control and doxorubicin (p=0.018). Everolimus alone also inhibited osteosarcoma PDOX growth compared to the control (p=0.04), but less than the combination. Palbociclib alone and doxorubicin were ineffective. There were no significant body-weight losses in any group. Only the palbociclib-everolimus combination induced extensive tumor necrosis observed histopathologically. CONCLUSION: The present study demonstrated that the combination of CDK4/6 and mTOR inhibitors can be a translatable approach for doxorubicin-resistant osteosarcoma in the clinic.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Osteossarcoma/tratamento farmacológico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adolescente , Animais , Neoplasias Ósseas/metabolismo , Modelos Animais de Doenças , Doxorrubicina/farmacologia , Everolimo/farmacologia , Feminino , Humanos , Camundongos , Camundongos Nus , Osteossarcoma/metabolismo , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Bull Cancer ; 108(9): 843-854, 2021 Sep.
Artigo em Francês | MEDLINE | ID: mdl-34154797

RESUMO

The historical median survival of advanced luminal breast cancer does not exceed four years. The deciphering of the mechanisms of resistance to hormone therapy has led to the development of inhibitors of cyclin D dependent kinases (CDK4 and 6). Three drugs, palbociclib, ribociclib and abemaciclib, very similar pharmacologically, have been evaluated in the context of pivotal, randomized phase III trials. Strikingly and regardless of the endocrine therapy backbone, and in both hormone-sensitive and hormone-resistant patients, the addition of a CDK4 / 6 inhibitor doubles progression-free survival with a hazard ratio always around 0.55. The benefit in overall survival begins to be demonstrated. This review presents all published results, as well as the main safety data.


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 , Aminopiridinas/uso terapêutico , Benzimidazóis/uso terapêutico , Neoplasias da Mama/enzimologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Ciclo Celular , Ensaios Clínicos Fase III como Assunto , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Feminino , Humanos , Piperazinas/uso terapêutico , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Purinas/uso terapêutico , Piridinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteínas de Ligação a Retinoblastoma/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
9.
J Med Chem ; 64(13): 9056-9077, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34110834

RESUMO

Control of the cell cycle through selective pharmacological inhibition of CDK4/6 has proven beneficial in the treatment of breast cancer. Extending this level of control to additional cell cycle CDK isoforms represents an opportunity to expand to additional tumor types and potentially provide benefits to patients that develop tumors resistant to selective CDK4/6 inhibitors. However, broad-spectrum CDK inhibitors have a long history of failure due to safety concerns. In this approach, we describe the use of structure-based drug design and Free-Wilson analysis to optimize a series of CDK2/4/6 inhibitors. Further, we detail the use of molecular dynamics simulations to provide insights into the basis for selectivity against CDK9. Based on overall potency, selectivity, and ADME profile, PF-06873600 (22) was identified as a candidate for the treatment of cancer and advanced to phase 1 clinical trials.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Quinase 2 Dependente de Ciclina/metabolismo , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/metabolismo , Cães , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Injeções Intravenosas , Camundongos , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
10.
Nat Commun ; 12(1): 3356, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099663

RESUMO

Since their discovery as drivers of proliferation, cyclin-dependent kinases (CDKs) have been considered therapeutic targets. Small molecule inhibitors of CDK4/6 are used and tested in clinical trials to treat multiple cancer types. Despite their clinical importance, little is known about how CDK4/6 inhibitors affect the stability of CDK4/6 complexes, which bind cyclins and inhibitory proteins such as p21. We develop an assay to monitor CDK complex stability inside the nucleus. Unexpectedly, treatment with CDK4/6 inhibitors-palbociclib, ribociclib, or abemaciclib-immediately dissociates p21 selectively from CDK4 but not CDK6 complexes. This effect mediates indirect inhibition of CDK2 activity by p21 but not p27 redistribution. Our work shows that CDK4/6 inhibitors have two roles: non-catalytic inhibition of CDK2 via p21 displacement from CDK4 complexes, and catalytic inhibition of CDK4/6 independent of p21. By broadening the non-catalytic displacement to p27 and CDK6 containing complexes, next-generation CDK4/6 inhibitors may have improved efficacy and overcome resistance mechanisms.


Assuntos
Ciclina D/metabolismo , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Animais , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Quinase 2 Dependente de Ciclina/genética , Quinase 2 Dependente de Ciclina/metabolismo , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/genética , Quinase 6 Dependente de Ciclina/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Células MCF-7 , Camundongos , Microscopia de Fluorescência , Piperazinas/farmacologia , Ligação Proteica , Piridinas/farmacologia , Epitélio Pigmentado da Retina/citologia , Epitélio Pigmentado da Retina/efeitos dos fármacos , Epitélio Pigmentado da Retina/metabolismo
11.
Expert Opin Drug Saf ; 20(8): 949-957, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34047239

RESUMO

BACKGROUND: We compared the efficacy and safety of combinations of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and PI3K/AKT/mTOR inhibitors as second-line treatment in postmenopausal women with HR+, HER2- metastatic breast cancer. METHODS: We searched the Medline, Embase, and Cochrane Library electronic databases for phase II/III randomized trials evaluating CDK4/6 and PI3K/AKT/mTOR inhibitors plus fulvestrant. We compared the results with a network meta-analysis. Study quality was assessed following the GRADE approach. Outcomes of interest were progression-free survival, overall response rate, overall survival and G3-4 adverse drug events (ADEs). RESULTS: Eight RCTs were identified in the network meta-analysis. PFS was significantly improved by treatment with abemaciclib plus fulvestrant and ribociclib plus fulvestrant compared to pictilisib plus fulvestrant. The ORR following treatment with abemaciclib plus fulvestrant, ribociclib plus fulvestrant, palbociclib plus fulvestrant, buparlisib plus fulvestrant, and alpelisib plus fulvestrant significantly differed from that observed following treatment with placebo plus fulvestrant. In terms of OS, compared with placebo plus fulvestrant, abemaciclib plus fulvestrant, ribociclib plus fulvestrant, and buparlisib plus fulvestrant had a significant difference. The risks of ADEs were similar among three CDK4/6 inhibitors. CONCLUSION: As second-line treatment, three CDK4/6 inhibitors showed superior clinical efficacy compared to other PI3K/AKT/mTOR inhibitors with comparable safety profiles.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Pós-Menopausa , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/patologia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Feminino , Humanos , Metástase Neoplásica , Inibidores de Fosfoinositídeo-3 Quinase/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor ErbB-2/metabolismo , Taxa de Sobrevida , Serina-Treonina Quinases TOR/antagonistas & inibidores , Resultado do Tratamento
12.
Front Immunol ; 12: 661737, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34025662

RESUMO

The recent advent of targeted and immune-based therapies has revolutionized the treatment of melanoma and transformed outcomes for patients with metastatic disease. The majority of patients develop resistance to the current standard-of-care targeted therapy, dual BRAF and MEK inhibition, prompting evaluation of a new combination incorporating a CDK4/6 inhibitor. Based on promising preclinical data, combined BRAF, MEK and CDK4/6 inhibition has recently entered clinical trials for the treatment of BRAFV600 melanoma. Interestingly, while BRAF- and MEK-targeted therapy was initially developed on the basis of potent tumor-intrinsic effects, it was later discovered to have significant immune-potentiating activity. Recent studies have also identified immune-related impacts of CDK4/6 inhibition, though these are less well defined and can be both immune-potentiating and immune-inhibitory. BRAFV600 melanoma patients are also eligible to receive immunotherapy, specifically checkpoint inhibitors against PD-1 and CTLA-4. The immunomodulatory activity of BRAF/MEK-targeted therapies has prompted interest in combination therapies incorporating these with immune checkpoint inhibitors, however recent clinical trials investigating this approach have produced variable results. Here, we summarize the immunomodulatory effects of BRAF, MEK and CDK4/6 inhibitors, shedding light on the prospective utility of this combination alone and in conjunction with immune checkpoint blockade. Understanding the mechanisms that underpin the clinical efficacy of these available therapies is a critical step forward in optimizing novel combination and scheduling approaches to combat melanoma and improve patient outcomes.


Assuntos
Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/imunologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunomodulação , Melanoma/tratamento farmacológico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Ensaios Clínicos como Assunto , Humanos , Melanoma/imunologia , Terapia de Alvo Molecular , Neoplasias Cutâneas/tratamento farmacológico
13.
Bull Cancer ; 108(5): 544-552, 2021 May.
Artigo em Francês | MEDLINE | ID: mdl-33820647

RESUMO

INTRODUCTION: The addition of palbociclib to endocrine therapy has been shown to improve progression free survival in hormone receptor positive metastatic breast cancer patients. This cyclin CDK4/6 inhibitor could expose patients to a grade 3-4 hematological toxicity, leading to treatment discontinuation or treatment interruption that is potentially associated with a lack of efficiency. The aim of this study was to identify predictive factors of severe early hematotoxicity (ESHT). METHODS: This retrospective cohort study included patients who started palbociclib in the Institut Sainte Catherine between December 1, 2016 and January 1, 2019 for the treatment of metastatic breast cancer. Individual data and hematological toxicity were collected from electronic medical records. ESHT was defined as the occurrence, during the first 3 cycles, of grade 4 or grade 3 hematological toxicity requiring palbociclib dose reduction. RESULTS: In total, 181 patients (180 females) were included; median age was 67 years. Forty-six patients (25.4%) experienced an ESHT. Predictive factors of ESHT in multivariate analysis were a performance status (PS) of 2 or more (P=0.024) and an history of radiotherapy of bone metastasis in the previous year (P=0.003). Before palbociclib initiation, a neutrophil count below 3.37g/L was predictive of ESHT with a sensibility of 76% and a specificity of 71%. CONCLUSIONS: ECOG PS, bone radiotherapy within the year and low baseline neutrophils count are associated with ESHT in palbociclib-treated metastatic breast cancer patients. These elements could be useful for a careful monitoring leading to adapted therapy.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Piperazinas/efeitos adversos , Piridinas/efeitos adversos , Trombocitopenia/induzido quimicamente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Neoplasias da Mama/química , Neoplasias da Mama/patologia , Neoplasias da Mama Masculina/tratamento farmacológico , Neoplasias da Mama Masculina/patologia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Feminino , Fulvestranto/efeitos adversos , Fulvestranto/uso terapêutico , Humanos , Letrozol/uso terapêutico , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neutropenia/induzido quimicamente , Piperazinas/uso terapêutico , Intervalo Livre de Progressão , Piridinas/uso terapêutico , Estudos Retrospectivos
14.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805656

RESUMO

17ß-estradiol (E2) exerts its physiological effects through the estrogen receptor α (i.e., ERα). The E2:ERα signaling allows the regulation of cell proliferation. Indeed, E2 sustains the progression of ERα positive (ERα+) breast cancers (BCs). The presence of ERα at the BC diagnosis drives their therapeutic treatment with the endocrine therapy (ET), which restrains BC progression. Nonetheless, many patients develop metastatic BCs (MBC) for which a treatment is not available. Consequently, the actual challenge is to complement the drugs available to fight ERα+ primary and MBC. Here we exploited a novel anti-estrogen discovery platform to identify new Food and Drug Administration (FDA)-approved drugs inhibiting E2:ERα signaling to cell proliferation in cellular models of primary and MBC cells. We report that the anti-fungal drugs clotrimazole (Clo) and fenticonazole (Fenti) induce ERα degradation and prevent ERα transcriptional signaling and proliferation in cells modeling primary and metastatic BC. The anti-proliferative effects of Clo and Fenti occur also in 3D cancer models (i.e., tumor spheroids) and in a synergic manner with the CDK4/CDK6 inhibitors palbociclib and abemaciclib. Therefore, Clo and Fenti behave as "anti-estrogens"-like drugs. Remarkably, the present "anti-estrogen" discovery platform represents a valuable method to rapidly identify bioactive compounds with anti-estrogenic activity.


Assuntos
Aminopiridinas/farmacologia , Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Clotrimazol/farmacologia , Receptor alfa de Estrogênio/antagonistas & inibidores , Imidazóis/farmacologia , Piperazinas/farmacologia , Piridinas/farmacologia , Antifúngicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/genética , Quinase 6 Dependente de Ciclina/metabolismo , Aprovação de Drogas , Descoberta de Drogas , Reposicionamento de Medicamentos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Estradiol/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , Proteólise , Transdução de Sinais , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia
15.
Eur J Med Chem ; 219: 113432, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-33857728

RESUMO

Cyclin-dependent kinases 4 and 6 (CDK4/6), which are involved in dynamic regulation of cell cycle, play an indispensable role in controlling the tumor growth. Here, based on the scaffold of palbociclib, we designed and synthesized a series of covalent CDK4/6 inhibitors that targeted amino acid Thr107. The optimized compound C-13 exhibited potent in vitro anticancer activity against CDK4/6 with high selectivity over CDK4/6. Moreover, C-13 showed significant tumor growth inhibition in MDA-MB-231 tumor xenograft model (TGI of 93.49% at dose of 40 mg/kg) without causing significant weight loss and toxicity during the treatment period.


Assuntos
Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Desenho de Fármacos , Piperazinas/química , Inibidores de Proteínas Quinases/química , Piridinas/química , Animais , Apoptose/efeitos dos fármacos , Sítios de Ligação , Pontos de Checagem do 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 , Camundongos , Camundongos Nus , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Piperazinas/metabolismo , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/metabolismo , Piridinas/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Molecules ; 26(8)2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33919867

RESUMO

Novel 6-bromo-coumarin-ethylidene-hydrazonyl-thiazolyl and 6-bromo-coumarin-thiazolyl-based derivatives were synthesized. A quantitative structure activity relationship (QSAR) model with high predictive power r2 = 0.92, and RMSE = 0.44 predicted five compounds; 2b, 3b, 5a, 9a and 9i to have potential anticancer activities. Compound 2b achieved the best ΔG of -15.34 kcal/mol with an affinity of 40.05 pki. In a molecular dynamic study 2b showed an equilibrium at 0.8 Å after 3.5 ns, while flavopiridol did so at 0.5 Å after the same time (3.5 ns). 2b showed an IC50 of 0.0136 µM, 0.015 µM, and 0.054 µM against MCF-7, A-549, and CHO-K1 cell lines, respectively. The CDK4 enzyme assay revealed the significant CDK4 inhibitory activity of compound 2b with IC50 of 0.036 µM. The selectivity of the newly discovered lead compound 2b toward localization in tumor cells was confirmed by a radioiodination biological assay that was done via electrophilic substitution reaction utilizing the oxidative effect of chloramine-t. 131I-2b showed good in vitro stability up to 4 h. In solid tumor bearing mice, the values of tumor uptake reached a height of 5.97 ± 0.82%ID/g at 60 min p.i. 131I-2b can be considered as a selective radiotheranostic agent for solid tumors with promising anticancer activity.


Assuntos
Antineoplásicos/farmacologia , Cumarínicos/farmacologia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Descoberta de Drogas , Radioisótopos do Iodo/química , Simulação de Dinâmica Molecular , Relação Quantitativa Estrutura-Atividade , Células A549 , Sequência de Aminoácidos , Animais , Antineoplásicos/química , Células CHO , Morte Celular/efeitos dos fármacos , Cumarínicos/química , Cricetulus , Quinase 2 Dependente de Ciclina/química , Quinase 4 Dependente de Ciclina/química , Quinase 4 Dependente de Ciclina/metabolismo , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Células MCF-7 , Simulação de Acoplamento Molecular , Distribuição Tecidual/efeitos dos fármacos
17.
Cancer Invest ; 39(5): 369-378, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33886387

RESUMO

OBJECTIVE: To evaluate the efficacy and safety of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors combined with endocrine therapy (ET) for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER-2-) advanced breast cancer (ABC) patients. METHODS: We searched clinical trials of CDK4/6 inhibitors combined with ET and calculated the clinical outcomes. RESULTS: HR+/HER-2- ABC patients treated with CDK4/6 inhibitors combined with ET had significantly prolonged progression-free survival (PFS) and improved objective response rate (ORR) and clinical benefit rate (CBR). CONCLUSIONS: CDK4/6 inhibitors combined with ET can bring more clinical benefits to ABC patients, and the safety profile is acceptable.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Receptores de Estrogênio/uso terapêutico , Receptores de Progesterona/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Feminino , Humanos
18.
Molecules ; 26(5)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803309

RESUMO

The inhibition of cyclin dependent kinases 4 and 6 plays a role in aromatase inhibitor resistant metastatic breast cancer. Three dual CDK4/6 inhibitors have been approved for the breast cancer treatment that, in combination with the endocrine therapy, dramatically improved the survival outcomes both in first and later line settings. The developments of the last five years in the search for new selective CDK4/6 inhibitors with increased selectivity, treatment efficacy, and reduced adverse effects are reviewed, considering the small-molecule inhibitors and proteolysis-targeting chimeras (PROTACs) approaches, mainly pointing at structure-activity relationships, selectivity against different kinases and antiproliferative activity.


Assuntos
Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Inibidores da Aromatase/farmacologia , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Terapia de Alvo Molecular/tendências
19.
Lancet Oncol ; 22(4): 489-498, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33794206

RESUMO

BACKGROUND: Alpelisib, a PI3Kα-selective inhibitor and degrader, plus fulvestrant showed efficacy in hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer in SOLAR-1; limited data are available in the post-cyclin-dependent kinase 4/6 inhibitor setting. BYLieve aimed to assess alpelisib plus endocrine therapy in this setting in three cohorts defined by immediate previous treatment; here, we report results from cohort A. METHODS: This ongoing, phase 2, multicentre, open-label, non-comparative study enrolled patients with hormone receptor-positive, HER2-negative, advanced breast cancer with tumour PIK3CA mutation, following progression on or after previous therapy, including CDK4/6 inhibitors, from 114 study locations (cancer centres, medical centres, university hospitals, and hospitals) in 18 countries worldwide. Participants aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 2 or less, with no more than two previous anticancer treatments and no more than one previous chemotherapy regimen, were enrolled in three cohorts. In cohort A, patients must have had progression on or after a CDK4/6 inhibitor plus an aromatase inhibitor as the immediate previous treatment. Patients received oral alpelisib 300 mg/day (continuously) plus fulvestrant 500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1. The primary endpoint was the proportion of patients alive without disease progression at 6 months per local assessment using Response Evaluation Criteria in Solid Tumors, version 1.1, in patients with a centrally confirmed PIK3CA mutation. This trial is registered with ClinicalTrials.gov, NCT03056755. FINDINGS: Between Aug 14, 2017, and Dec 17, 2019 (data cutoff), 127 patients with at least 6 months' follow-up were enrolled into cohort A. 121 patients had a centrally confirmed PIK3CA mutation. At data cutoff, median follow-up was 11·7 months (IQR 8·5-15·9). 61 (50·4%; 95% CI 41·2-59·6) of 121 patients were alive without disease progression at 6 months. The most frequent grade 3 or worse adverse events were hyperglycaemia (36 [28%] of 127 patients), rash (12 [9%]), and rash maculopapular (12 [9%]). Serious adverse events occurred in 33 (26%) of 127 patients. No treatment-related deaths were reported. INTERPRETATION: BYLieve showed activity of alpelisib plus fulvestrant with manageable toxicity in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer, after progression on a CDK4/6 inhibitor plus an aromatase inhibitor. FUNDING: Novartis Pharmaceuticals.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/genética , Quinase 4 Dependente de Ciclina/genética , Quinase 6 Dependente de Ciclina/genética , Tiazóis/administração & dosagem , Adolescente , Adulto , Idoso , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Antagonistas do Receptor de Estrogênio/administração & dosagem , Feminino , Fulvestranto/administração & dosagem , Humanos , Pessoa de Meia-Idade , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética , Receptores de Estrogênio/genética , Receptores de Progesterona/antagonistas & inibidores , Receptores de Progesterona/genética
20.
Cancer Cell ; 39(3): 307-309, 2021 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-33689702

RESUMO

CDK4/6 inhibitors have transformed the treatment of metastatic estrogen-receptor-positive HER2-negative breast cancer, with efficacy found consistently for three different inhibitors. Recent adjuvant trials of CDK4/6 inhibitors in early stage breast cancer have produced discordant results, shedding light on their clinical utility and future trial design.


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 , Neoplasias da Mama/metabolismo , Feminino , Humanos , Intervalo Livre de Progressão , Receptor ErbB-2/metabolismo
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