RESUMO
Palbociclib and ribociclib an orally bioavailable, potent cyclin-dependent kinase 4/6 inhibitors, with low oral bioavailability due to substrate specificity towards CYP3A and P-glycoprotein. Thus, current research aims to examine the effect of a bioenhancer (naringin), on oral pharmacokinetics of palbociclib and ribociclib. Naringin's affinity for CYP3A4 and P-glycoprotein was studied using molecular docking; its impact on palbociclib/ribociclib CYP3A metabolism and P-glycoprotein-mediated efflux was examined using in vitro preclinical models; and its oral pharmacokinetics in rats were assessed following oral administration of palbociclib/ribociclib in presence of naringin (50 and 100 mg/kg). Naringin binds optimally to both proteins with the highest net binding energy of - 1477.23 and - 1607.47 kcal/mol, respectively. The microsomal intrinsic clearance of palbociclib and ribociclib was noticeably reduced by naringin (5-100 µM), by 3.0 and 2.46-folds, respectively. Similarly, naringin had considerable impact on the intestinal transport and efflux of both drugs. The pre-treatment with 100 mg/kg naringin increased significantly (p < 0.05) the oral exposure of palbociclib (2.0-fold) and ribociclib (1.95-fold). Naringin's concurrent administration of palbociclib and ribociclib increased their oral bioavailability due to its dual inhibitory effect on CYP3A4 and P-glycoprotein; thus, concurrent naringin administration may represent an innovative strategy for enhancing bioavailability of cyclin-dependent kinase inhibitors.
Assuntos
Disponibilidade Biológica , Quinase 6 Dependente de Ciclina , Flavanonas , Inibidores de Proteínas Quinases , Animais , Humanos , Ratos , Administração Oral , Aminopiridinas/farmacocinética , Aminopiridinas/farmacologia , Aminopiridinas/administração & dosagem , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Biomelhoradores/farmacologia , Células CACO-2 , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Citocromo P-450 CYP3A/metabolismo , Inibidores das Enzimas do Citocromo P-450/farmacologia , Inibidores das Enzimas do Citocromo P-450/administração & dosagem , Flavanonas/administração & dosagem , Flavanonas/farmacologia , Simulação de Acoplamento Molecular , Permeabilidade , Piperazinas/farmacocinética , Piperazinas/farmacologia , Piperazinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Purinas/farmacocinética , Purinas/administração & dosagem , Purinas/farmacologia , Piridinas/farmacocinética , Piridinas/farmacologia , Piridinas/administração & dosagem , Ratos Sprague-DawleyAssuntos
Neoplasias da Mama , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Inibidores de Proteínas Quinases , Humanos , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Neoplasias da Mama/tratamento farmacológico , Feminino , Inibidores de Proteínas Quinases/uso terapêutico , Antineoplásicos/uso terapêutico , Terapia de Alvo MolecularRESUMO
PURPOSE: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy have demonstrated significant clinical benefits in progression-free and overall survival. This study investigates the outcomes associated with two kinds of CDK4/6i in patients with hormone receptor (HR)-positive metastatic and relapsed breast cancer to inform real-world evidence of treatment strategies. METHODS: This retrospective study included 340 Taiwanese patients with HR-positive advanced breast cancer from the Taipei Veterans General Hospital, between 2018 and 2023. We analyzed patient characteristics, treatment strategies and outcomes associated with two CDK4/6i. The efficacy of patients who experienced economic burden and interrupted CDK4/6i treatment after 2 years of National Health Insurance (NHI) reimbursement was also investigated. RESULTS: Patients receiving ribociclib and palbociclib showed no significant differences in age, histology, body mass index(BMI), or pathologic status. The distribution of disease status and endocrine therapy partners was comparable between the two groups. Dose reduction was similar, while patients with palbociclib tended to discontinue CDK4/6i usage, and those with ribociclib tended to switch to the other CDK4/6i or endocrine partners. There was no significant difference in progression-free survival (PFS) between the two CDK4/6i in the first-line setting. Adverse prognostic factors were increasing HER2 IHC score, higher Ki-67 levels, visceral and liver metastasis, prior chemotherapy, and endocrine therapy resistance, while higher BMI, bone-only metastasis, and letrozole treatment were associated with a lower risk of progression. The limited follow-up time in our study was insufficient to assess the outcomes of patients treated with interrupted CDK4/6i for up to two years under the NHI reimbursement policy. CONCLUSION: Treatment outcomes between the two types of CDK4/6i did not differ significantly, indicating the safety and efficacy of CDK4/6i for the Asian population. Ribociclib and palbociclib showed similar efficacy in PFS in the real-world setting.
Assuntos
Aminopiridinas , Neoplasias da Mama , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Piperazinas , Inibidores de Proteínas Quinases , Purinas , Piridinas , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Pessoa de Meia-Idade , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Piridinas/uso terapêutico , Estudos Retrospectivos , Idoso , Piperazinas/uso terapêutico , Aminopiridinas/uso terapêutico , Purinas/uso terapêutico , Taiwan , Inibidores de Proteínas Quinases/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Resultado do Tratamento , Metástase Neoplásica , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Povo AsiáticoRESUMO
BACKGROUND: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors marked a milestone in the breast cancer treatment. Due to the potential impact of adverse effects on treatment decisions and patient outcomes, careful consideration of the varying toxicities of CDK4/6 inhibitors is crucial, as three inhibitors-palbociclib, abemaciclib, and ribociclib-have been approved with differences in adverse event profiles. However, limitations in clinical trials call for urgent real-world safety studies to evaluate and compare the risk of adverse events (AEs) among these CDK4/6 inhibitors. Therefore, this study aimed to analyze AEs of CDK4/6 inhibitors and provide insights for clinical drug selection, using real world database. METHODS: The AEs of CDK4/6 inhibitors in the FDA Adverse Event Reporting System (2015-2022) were analyzed. Four disproportionality methods were used to detect safety signals: reporting odds ratio (ROR), proportional reporting ratio, Bayesian Confidence Neural Network Propagation, and Multi-Item Gamma Poisson Shrinker. Venn analysis was used to compare and select common and specific AEs. RESULTS: This study included 73,042 patients treated with palbociclib, 25,142 with ribociclib, and 7563 with abemaciclib. All three inhibitors had 27 common AEs. Palbociclib exhibited the highest ROR for hematologic toxicities, while ribociclib showed the highest ROR for macrocytosis, nail disorders, and hepatic lesions. Abemaciclib displayed the highest ROR for mucosal toxicity. Common signals for both palbociclib and ribociclib included hematologic toxicities, decreased immune responsiveness, and aphthous ulcers. Myelosuppression, oral pain, and pseudocirrhosis were common signals for palbociclib and abemaciclib. Anemia, hepatotoxicity, and pneumonitis were observed as common signals for ribociclib and abemaciclib. Furthermore, specific AEs associated with palbociclib included fatigue, alopecia, and stomatitis. For ribociclib, specific AEs included electrocardiogram QT prolongation, thrombocytopenia, and decreased hemoglobin. Abemaciclib was specifically linked to diarrhea, vomiting, and interstitial lung disease. CONCLUSION: Our analysis revealed that palbociclib showed a higher risk of hematologic toxicity. Ribociclib showed higher risks of hepatotoxicity, nephrotoxicity, and QT prolongation. Abemaciclib showed higher risks of hepatotoxicity, gastrointestinal effects, interstitial lung disease, and thrombosis. These findings provide valuable insights for CDK4/6 inhibitor selection.
Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos , Aminopiridinas , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Farmacovigilância , Piperazinas , Inibidores de Proteínas Quinases , Purinas , Piridinas , United States Food and Drug Administration , Humanos , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Estados Unidos/epidemiologia , Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Purinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Piperazinas/efeitos adversos , Piperazinas/uso terapêutico , Aminopiridinas/efeitos adversos , Piridinas/efeitos adversos , Benzimidazóis/efeitos adversos , Estudos de Casos e Controles , Antineoplásicos/efeitos adversos , FemininoRESUMO
OBJECTIVE: To evaluate the impact of CDK4/6 inhibitors on erythrocyte mean corpuscular volume (MCV) change and its possible correlation with progression-free survival (PFS) and overall survival (OS). STUDY DESIGN: Observational study. Place and Duration of the Study: Department of Medical Oncology, Kahramanmaras Necip Fazil City Hospital, Kahramanmaras, Turkiye, between January 2020 and 2023. METHODOLOGY: The data of 74 patients with HR (+) HER2 (-) metastatic breast cancer were analysed retrospectively. MCV and other complete blood count metrics were noted before and after the treatment. The first post-treatment evaluation was performed at three months. The median ΔMCV values at the third month after treatment-baseline were calculated. RESULTS: The patients were all females, with a median age of 55 years (between 35 and 80). Prior to the therapy, the baseline median MCV level was 90.4 (min-max: 77.3-113.2). After three months, the median MCV level was 95 (min-max: 84.3-115.3). Moreover, 7.15 was the median ΔMCV level. Regarding PFS (16.53 vs. 15.26 months) (p = 0.13) and OS (21.46 vs. 17.83 months) (p = 0.08), there was no statistically significant difference seen between the group with ΔMCV ≥7.15 and the group with ΔMCV <7.15. CONCLUSION: CDK4/6 inhibitors led to an increase in MCV but there was no significant difference between PFS or OS and the increase in MCV. To figure out whether the rise in MCV represents a prognostic or predictive marker, further research is required. KEY WORDS: Breast cancer, CDK4/6 inhibitors, Mean corpuscular volume, Prognosis.
Assuntos
Neoplasias da Mama , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Índices de Eritrócitos , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/sangue , Pessoa de Meia-Idade , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Idoso , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Estudos Retrospectivos , Adulto , Inibidores de Proteínas Quinases/uso terapêutico , Idoso de 80 Anos ou mais , Prognóstico , Piperazinas/uso terapêutico , Piridinas/uso terapêuticoRESUMO
BACKGROUND: This study was designed to evaluate the effect of progesterone receptor (PR) status on the prognosis of advanced estrogen receptor (ER)-high human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients receiving CDK4/6 inhibitor combined with endocrine as first-line therapy. METHODS: Advanced ER-high HER2-negative breast cancer patients who were admitted to Harbin Medical University Cancer Hospital and received cyclin-dependent kinase (CDK)4/6 inhibitor combined with endocrine as first-line therapy were included for analysis. Patients were divided into PR-high group (11-100%), PR-low group (1-10%), and PR-negative group (< 1%) according to the expression of PR. Chi-square test was used to analyze the correlation of variables between groups. COX regression analysis were used to analyze the risk factors of survival. Kaplan-Meier survival curve was used to analyze the differences of progression-free survival (PFS) and overall survival (OS) between groups. RESULTS: Among the 152 patients, 72 were PR-high, 32 were PR-low, and 48 were PR-negative. Compared with PR-negative group, the proportions of disease-free survival (DFS) ≥ 5 years and Ki-67 index ≤ 30% in PR-low group and PR-high group were significant higher. PR-negative patients were more likely to occur first-line progression of disease within 24 months (POD24) than PR-high(P = 0.026). Univariate and multivariate analysis showed that PR-negative and first-line POD24 occurrence were risk factors for survival. Survival curve analysis showed that compared with PR-high group, the PFS and OS were significantly lower in PR-negative group (P = 0.001, P = 0.036, respectively). Patients with first-line POD24 had shorter OS in the overall population as well as in subgroups stratified by PR status. CONCLUSIONS: PR-negative and first-line POD24 occurrence were risk factors of advanced ER-high HER2-negative breast cancer patients receiving CDK4/6 inhibitor combined with endocrine as first-line therapy. PR-negative patients had shortest PFS and OS. Regardless of PR status, first-line POD24 occurrence predicted shorter OS.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Receptor ErbB-2 , Receptores de Estrogênio , Receptores de Progesterona , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Receptor ErbB-2/metabolismo , Receptores de Progesterona/metabolismo , Pessoa de Meia-Idade , Receptores de Estrogênio/metabolismo , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Prognóstico , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Idoso , Inibidores de Proteínas Quinases/uso terapêutico , Estimativa de Kaplan-Meier , Estudos Retrospectivos , Antineoplásicos Hormonais/uso terapêuticoRESUMO
BACKGROUND: The emergence of cyclin-dependent kinases 4/6 inhibitors (CDK4/6i) represented a major breakthrough in the treatment of breast cancer over the past decade. In both clinical trials and real-world settings, it was observed that patients using CDK4/6i might experience psychiatric adverse events (PAEs). Herein, we conducted a pharmacovigilance study to comprehensively assess the correlation between CDK4/6i and PAEs. METHOD: We obtained individual case safety reports submitted to the FDA Adverse Events Reporting System (FAERS) during the period from January 2015 to December 2023. In disproportionality analysis, the reporting odds ratio (ROR) and information component (IC) values were calculated for each adverse event-drug combination. Univariate logistic regression analysis was utilized to explore factors associated with PAEs following CDK4/6i treatment. RESULTS: A total of 95,591 reports related to CDK4/6i were identified, with 6.72% reporting PAEs, and this proportion exhibited an annual upward trend. Based on the ROR and IC values, 17 categories of PAEs were defined as CDK4/6i-related PAEs. Among these PAEs, insomnia, stress, eating disorder, depressed mood, and sleep disorder were very common, each accounting for over 10% of CDK4/6i reports. Ribociclib showed the highest risk signal of CDK4/6i-related PAEs (ROR = 1.89[1.75-2.04], IC025 = 0.79), followed by palbociclib (ROR = 1.47[1.41-1.53], IC025 = 0.49), while abemaciclib did not exhibit a significant signal (ROR = 0.52[0.44-0.62], IC025 = -1.13). Female sex, younger age and weight exceeding 80 kg were significant risk factors for the incidence of CDK4/6i-related PAEs. CONCLUSIONS: Using data from a real-world, large-scale spontaneous reporting system for adverse drug reactions, our study delineated the spectrum of PAEs to CDK4/6i. This potentially offered valuable insights for healthcare professionals to manage the risk of PAEs in patients receiving CDK4/6i treatment, particularly those with psychiatric disorders.
Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Transtornos Mentais , Farmacovigilância , Inibidores de Proteínas Quinases , United States Food and Drug Administration , Humanos , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Feminino , Masculino , Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Estados Unidos/epidemiologia , Pessoa de Meia-Idade , Idoso , Transtornos Mentais/induzido quimicamente , Transtornos Mentais/epidemiologia , Adulto , United States Food and Drug Administration/tendências , Inibidores de Proteínas Quinases/efeitos adversos , Adulto Jovem , Adolescente , Idoso de 80 Anos ou maisRESUMO
The fact that the human epidermal growth factor receptor 2 (HER2)-low group, historically classified as HER2 negative in breast cancer histology, benefited from HER2-targeted treatments similarly to the HER2-positive group indicates that this group has a distinct histology from the HER2-0 group. The effectiveness of cyclin-dependent kinase 4/6 inhibitors, which are the standard first-line treatment for hormone receptor-positive, HER2-negative advanced breast cancer, in this newly defined histological subgroup remains a topic of debate. In our study, we examined the impact of HER2 status on the efficacy of CDK4/6 inhibitors. Our study is a retrospective, multicenter, real-world data analysis. One hundred sixty patients were included in the study. The relationship between HER2 status and other clinical-pathological features, as well as progression-free survival, was examined. Median follow-up was 20.33â ±â 0.98 months. The mPFS could not be reached. All patients exhibited positive estrogen receptor expression. Among the patients, 111 (69.4%) were categorized as HER2-0, and 49 (30.6%) as HER2-low. The 24-month progression-free survival rates were similar between HER2-0 and HER2-low patients (60.6% vs 65.3%, hormone receptor: 1.18, CI: 0.67-2.20, Pâ =â .554). We established that the mPFS achieved with cyclin-dependent kinase 4/6 inhibitors as a first-line therapy for patients with advanced breast cancer is unaffected by HER2 status.
Assuntos
Neoplasias da Mama , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Receptor ErbB-2 , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/mortalidade , Receptor ErbB-2/metabolismo , Receptor ErbB-2/antagonistas & inibidores , Estudos Retrospectivos , Pessoa de Meia-Idade , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Idoso , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Adulto , Intervalo Livre de Progressão , Receptores de Estrogênio/metabolismoRESUMO
BACKGROUND: Current standard treatment for metastatic breast cancer (MBC) involves cyclin-dependent kinase 4/6 (CDK4/6) inhibitors with endocrine therapy, showing potential in enhancing anti-tumor immune responses. CASE REPORT: This report details a clinical case of MBC where palbociclib was co-administered with letrozole. The integration of allogeneic tumor vaccination to this treatment led to heightened interferon-γ production, expansion of CD8+ and NK cell populations, and positive delayed-type hypersensitivity reactions, indicating successful development of anti-tumor immunity. The induced production of interferon-γ by tumor vaccination was associated with manageable modulation of sensitivity to palbociclib-letrozole therapy. Administration of the BioNTech/Pfizer Covid-19 vaccine compromised the anti-tumor immune response by reducing cytotoxic cell populations and increasing immunosuppressive cytokine production. The patient undergoing combined treatment achieved a progressive-free survival of 42 months. CONCLUSION: Incorporating active tumor vaccination with CDK4/6 inhibitor therapy presents a feasible approach for metastatic breast cancer. The precise regulation of the microenvironment emerges as a crucial factor and warrants careful consideration.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama , Vacinas Anticâncer , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Piperazinas , Piridinas , Humanos , Feminino , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/imunologia , Piperazinas/administração & dosagem , Piperazinas/uso terapêutico , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Letrozol/administração & dosagem , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/imunologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Pessoa de Meia-Idade , Interferon gama/metabolismoAssuntos
Neoplasias da Mama , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Inibidores de Proteínas Quinases , Receptor ErbB-2 , Receptores de Estrogênio , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Feminino , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Receptor ErbB-2/metabolismo , Receptor ErbB-2/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , IdosoRESUMO
Cyclin-dependent kinases 4 and 6 (CDK4/6) play a pivotal role in cell cycle and cancer development. Targeting CDK4/6 has demonstrated promising effects against breast cancer. However, resistance to CDK4/6 inhibitors (CDK4/6i), such as palbociclib, remains a substantial challenge in clinical settings. Using high-throughput combinatorial drug screening and genomic sequencing, we find that the microphthalmia-associated transcription factor (MITF) is activated via O-GlcNAcylation by O-GlcNAc transferase (OGT) in palbociclib-resistant breast cancer cells and tumors. Mechanistically, O-GlcNAcylation of MITF at Serine 49 enhances its interaction with importin α/ß, thus promoting its translocation to nuclei, where it suppresses palbociclib-induced senescence. Inhibition of MITF or its O-GlcNAcylation re-sensitizes resistant cells to palbociclib. Moreover, clinical studies confirm the activation of MITF in tumors from patients who are palbociclib-resistant or undergoing palbociclib treatment. Collectively, our studies shed light on the mechanism regulating palbociclib resistance and present clinical evidence for developing therapeutic approaches to treat CDK4/6i-resistant breast cancer patients.
Assuntos
Neoplasias da Mama , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Resistencia a Medicamentos Antineoplásicos , Fator de Transcrição Associado à Microftalmia , N-Acetilglucosaminiltransferases , Piperazinas , Piridinas , Humanos , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Neoplasias da Mama/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Quinase 6 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Fator de Transcrição Associado à Microftalmia/metabolismo , Fator de Transcrição Associado à Microftalmia/genética , Feminino , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Piperazinas/farmacologia , Piridinas/farmacologia , Linhagem Celular Tumoral , N-Acetilglucosaminiltransferases/metabolismo , N-Acetilglucosaminiltransferases/antagonistas & inibidores , N-Acetilglucosaminiltransferases/genética , Animais , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The aim of this study is to share real-life data on the increase in creatinine due to CDK 4/6 inhibitor treatment and patients diagnosed with HR+/HER2-MBC and treated with ribociclib or palbociclib combined with ET were included in the study. While creatinine increase was observed in 17.9% (n = 19) of the 106 patients in the study population, 8.5% (n = 9) had Grade 1, 8.5% (n = 8) had Grade 2, and % 0.9 (n = 1) had Grade 3 creatinine elevation. The increase in creatinine occurred in 25% (n = 12) of ribociclib users and 12.1% (n = 7) of palbociclib users. No patient required a dose reduction or discontinuation of treatment due to elevated creatinine. Of the patients with high creatinine levels, 36.8% (n = 7) were over 65 years of age. Those with multiple comorbidities, blood urea nitrogen (BUN) >13.5 mg/dl, creatinine >0.66 mg/dl, BUN/creatinine ratio >19.95, glomerular filtration rate (GFR) >96.05 ml/min, and uric acid >4.69mg/dl. It was observed that the increase in the creatinine level was statistically significant (p <0.001). In conclusion, this study revealed that the increase in the serum creatinine secondary to ribociclib and palbociclib treatments is associated with kidney function tests and the number of concomitant diseases. Key Words: CDK 4/6 inhibitor, Creatinine elevation, Palbociclib, Ribociclib.
Assuntos
Aminopiridinas , Creatinina , Quinase 4 Dependente de Ciclina , Piperazinas , Purinas , Piridinas , Humanos , Purinas/efeitos adversos , Purinas/administração & dosagem , Purinas/uso terapêutico , Creatinina/sangue , Piperazinas/efeitos adversos , Piperazinas/administração & dosagem , Piperazinas/uso terapêutico , Aminopiridinas/efeitos adversos , Aminopiridinas/administração & dosagem , Aminopiridinas/uso terapêutico , Feminino , Piridinas/efeitos adversos , Piridinas/administração & dosagem , Pessoa de Meia-Idade , Idoso , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Neoplasias da Mama/tratamento farmacológico , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Adulto , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , MasculinoRESUMO
The synthesis, biochemical evaluation and radiosynthesis of a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor and radioligand was performed. NT431, a newly synthesized 4-fluorobenzyl-abemaciclib, exhibited high potency to CDK4/6 and against four cancer cell lines with IC50 similar to that of the parent abemaciclib. We performed a two-step one-pot radiosynthesis to produce [18F]NT431 with good radiochemical yield (9.6 ± 3%, n = 3, decay uncorrected), high radiochemical purity (>95%), and high molar activity (>370 GBq/µmol (>10.0 Ci/µmol). In vitro autoradiography confirmed the specific binding of [18F]NT431 to CDK4/6 in brain tissues. Dynamic PET imaging supports that both [18F]NT431 and the parent abemaciclib crossed the BBB albeit with modest brain uptake. Therefore, we conclude that it is unlikely that NT431 or abemaciclib (FDA approved drug) can accumulate in the brain in sufficient concentrations to be potentially effective against breast cancer brain metastases or brain cancers. However, despite the modest BBB penetration, [18F]NT431 represents an important step towards the development and evaluation of a new generation of CDK4/6 inhibitors with superior BBB penetration for the treatment and visualization of CDK4/6 positive tumors in the CNS. Also, [18F]NT431 may have potential application in peripheral tumors such as breast cancer and other CDK4/6 positive tumors.
Assuntos
Aminopiridinas , Benzimidazóis , Neoplasias Encefálicas , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Tomografia por Emissão de Pósitrons , Inibidores de Proteínas Quinases , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/metabolismo , Humanos , Tomografia por Emissão de Pósitrons/métodos , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/enzimologia , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/metabolismo , Linhagem Celular Tumoral , Benzimidazóis/farmacologia , Benzimidazóis/química , Aminopiridinas/química , Aminopiridinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Animais , Compostos Radiofarmacêuticos/química , Radioisótopos de Flúor/química , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Camundongos , FemininoRESUMO
The comprehensive genomic analysis of the head and neck squamous cell carcinoma (HNSCC) oncogenome revealed the frequent loss of p16INK4A (CDKN2A) and amplification of cyclin D1 genes in most human papillomavirus-negative HNSCC lesions. However, cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have shown modest effects in the clinic. The aberrant activation of the PI3K/mTOR pathway is highly prevalent in HNSCC, and recent clinical trials have shown promising clinical efficacy of mTOR inhibitors (mTORi) in the neoadjuvant and adjuvant settings but not in patients with advanced HNSCC. By implementing a kinome-wide CRISPR/Cas9 screen, we identified cell-cycle inhibition as a synthetic lethal target for mTORis. A combination of mTORi and palbociclib, a CDK4/6-specific inhibitor, showed strong synergism in HNSCC-derived cells in vitro and in vivo. Remarkably, we found that an adaptive increase in cyclin E1 (CCNE1) expression upon palbociclib treatment underlies the rapid acquired resistance to this CDK4/6 inhibitor. Mechanistically, mTORi inhibits the formation of eIF4G-CCNE1 mRNA complexes, with the consequent reduction in mRNA translation and CCNE1 protein expression. Our findings suggest that mTORi reverts the adaptive resistance to palbociclib. This provides a multimodal therapeutic option for HNSCC by cotargeting mTOR and CDK4/6, which in turn may halt the emergence of palbociclib resistance. SIGNIFICANCE: A kinome-wide CRISPR/Cas9 screen identified cell-cycle inhibition as a synthetic lethal target of mTORis. A combination of mTORi and palbociclib, a CDK4/6-specific inhibitor, showed strong synergistic effects in HNSCC. Mechanistically, mTORis inhibited palbociclib-induced increase in CCNE1.
Assuntos
Sistemas CRISPR-Cas , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Resistencia a Medicamentos Antineoplásicos , Neoplasias de Cabeça e Pescoço , Piperazinas , Piridinas , Carcinoma de Células Escamosas de Cabeça e Pescoço , Humanos , 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 , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Piridinas/farmacologia , Camundongos , Animais , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/metabolismo , Linhagem Celular Tumoral , Inibidores de MTOR/farmacologia , Inibidores de MTOR/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Serina-Treonina Quinases TOR/metabolismo , Ciclina E/genética , Ciclina E/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Mutações Sintéticas Letais , Proteínas OncogênicasRESUMO
Breast cancer (BC) cells have a high risk of metastasis due to epithelial-mesenchymal transition (EMT). Palbociclib (CDK4/6 inhibitor) is an approved drug for BC treatment. However, the drug resistance and metastasis can impair the treatment outcome of Palbociclib. Understanding the mechanisms of EMT and Palbociclib drug resistance in BC is conducive to the formulation of novel therapeutic strategy. Here, we investigated the role of circHIAT1/miR-19a-3p/CADM2 axis in modulating EMT and Palbociclib resistance in BC. circHIAT1 and CADM2 were down-regulated in BC tissues and cell lines, and miR-19a-3p showed an up-regulation. circHIAT1 could interact with miR-19a-3p and suppress its activity, while miR-19a-3p functioned to negatively regulate CADM2. Forced over-expression of circHIAT1 could impaired the EMT status and migratory ability of BC cells, and this effect was inhibited by miR-19a-3p mimic. In addition, we also generated Palbociclib resistant BC cells, and showed that circHIAT1 and CADM2 were down-regulated in the resistant BC cells while miR-19a-3p showed an up-regulation. Forced circHIAT1 over-expression re-sensitized BC cells to Palbociclib treatment. Quercetin, a bioactive flavonoid, could suppressed the migration and invasion of BC cells, and re-sensitized BC cells to Palbociclib. The anti-cancer effect of quercetin could be attributed to its regulatory effect on circHIAT1/miR-19a-3p/CADM2 axis. In vivo tumorigenesis experiment further revealed that quercetin administration enhanced the anti-cancer effect of Palbociclib, an effect was dependent on the up-regulation of circHIAT1 by quercetin. In summary, this study identified quercetin as a potential anti-cancer compound to reverse Palbociclib resistance and impair EMT in BC cells by targeting circHIAT1/miR-19a-3p/CADM2 axis.
Assuntos
Neoplasias da Mama , Quinase 6 Dependente de Ciclina , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , MicroRNAs , Piperazinas , Piridinas , Quercetina , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Feminino , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Piridinas/farmacologia , Piperazinas/farmacologia , Linhagem Celular Tumoral , Quercetina/farmacologia , Animais , Camundongos , Quinase 6 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Movimento Celular/efeitos dos fármacos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Camundongos Nus , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
INTRODUCTION: Cyclin-dependent protein kinase 4/6 (CDK4/6) is a class of serine/threonine protein kinases that plays a key role in the regulation of the cell cycle. CDK4/6 is highly expressed in cancers such as breast cancer, melanoma, and non-small cell lung cancer (NSCLC). Currently, a variety of CDK4/6 inhibitors have been developed, aiming to develop effective inhibitors to solve CDK4/6 resistance and toxicity. AREAS COVERED: This article searches patents through Espacenet and reviews the development of widely studied CDK inhibitors and FDA-approved CDK4/6 inhibitors, as well as the latest progress of patented inhibitors with good inhibitory activity against CDK4/6 from 2020 to now. EXPERT OPINION: CDK4/6 is highly expressed in many tumors and has become an important anti-tumor target. Among the patents from 2020 to the present, many inhibitors have good kinase inhibitory effects on CDK4/6 and also show great development potential in anti-tumor. However, there is still an urgent need to develop novel CDK4/6 inhibitors that address challenges such as drug resistance, toxicity, and selectivity.
Assuntos
Antineoplásicos , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Desenvolvimento de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Neoplasias , Patentes como Assunto , Inibidores de Proteínas Quinases , Humanos , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Antineoplásicos/farmacologia , AnimaisRESUMO
CDK4/6 inhibitors are oral agents inhibiting key molecules of the cell cycle regulation. In patients with endocrine receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer, the combination of CDK4/6 inhibitors with endocrine therapy is an effective treatment in the metastatic setting. Now, two studies in the adjuvant setting - MonarchE (2 years of abemaciclib) and NATALEE (3 years of ribociclib) - report positive invasive disease-free survival. Here, we re-evaluate these seminal trials. First, an excess drop-out or loss-to-follow up occurred early in the control arms of both studies. Since both trials are open-label, there is concern that the patients who drop-out do not do so at random but based on socioeconomic factors and alternative options. Is it possible that the results merely appear favorable due to loss to follow up? Based on re-constructed Kaplan-Meier curves, we concluded the results of these studies remain fragile, being prone to informative censoring. Secondly, adverse events were notably higher in both trials, and some of them, like COVID-19 related deaths in NATALEE, raise serious concerns. Third, the potential costs associated with CDK4/6 inhibition given as adjuvant therapy are unprecedented. The NATALEE strategy, in particular, could affect up to 35 % of patients with newly diagnosed breast cancer, which is the cancer with the highest incidence worldwide. Without confirmatory data based on a placebo-controlled trial, or better identification of patients that would benefit from the addition of CDK4/6 inhibitors in the adjuvant setting, we argue against their routine use as adjuvant therapy in ER+ /HER2- early breast cancer.
Assuntos
Neoplasias da Mama , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Inibidores de Proteínas Quinases , Feminino , Humanos , Aminopiridinas/uso terapêutico , Aminopiridinas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/uso terapêutico , Benzimidazóis/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Purinas/uso terapêutico , Purinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, including abemaciclib, have been approved for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced, and metastatic breast cancer. Despite the high therapeutic efficacy of CDK4/6 inhibitors, they are associated with various adverse effects, including potentially fatal interstitial lung disease. Therefore, a combination of CDK4/6 inhibitors with letrozole or fulvestrant has been attempted but has demonstrated limitations in reducing adverse effects, highlighting the need to develop new combination therapies. This study proposes a combination strategy using CDK4/6 inhibitors and tricyclic antidepressants to enhance the therapeutic outcomes of these inhibitors while reducing their side effects. The therapeutic efficacies of abemaciclib and desipramine were tested in different cancer cell lines (H460, MCF7, and HCT-116). The antitumor effects of the combined abemaciclib and desipramine treatment were evaluated in a xenograft colon tumor model. In vitro cell studies have shown the synergistic anticancer effects of combination therapy in the HCT-116 cell line. The combination treatment significantly reduced tumor size compared with control or single treatment without causing apparent toxicity to normal tissues. Although additional in vivo studies are necessary, this study suggests that the combination therapy of abemaciclib and desipramine may represent a novel therapeutic approach for treating solid tumors.
Assuntos
Aminopiridinas , Benzimidazóis , Desipramina , Sinergismo Farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto , Humanos , Benzimidazóis/farmacologia , Benzimidazóis/administração & dosagem , Aminopiridinas/farmacologia , Aminopiridinas/administração & dosagem , Animais , Camundongos , Desipramina/farmacologia , Linhagem Celular Tumoral , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/metabolismo , Proliferação de Células/efeitos dos fármacos , Camundongos Nus , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/metabolismo , Células MCF-7 , Células HCT116 , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/administração & dosagem , Camundongos Endogâmicos BALB CRESUMO
In search of potential anticancer agents, we synthesized SNO-donor salicylaldimine main ligand-based Pt(II) complexes bearing NH3 as co-ligand at trans-position (C1-C6). These complexes showed similarity in structure with transplatin as the two N donor atoms of the main ligand and NH3 co-ligand were coordinated to Pt in trans position to each other. Each complex with different substituents on the main ligand was characterized thoroughly by detailed spectroscopic and spectrophotometric methods. Four of these complexes were studied in solid state by single crystal X-ray analysis. The stability of reference complex C1 was measured in solution state in DMSOd6 or its mixture with D2O using 1H NMR methods. These complexes were further investigated for their anticancer activity in triple-negative-breast (TNBC) cells including MDA-MB-231, MDA-MB-468 and MDA-MB-436 cells. All these complexes showed satisfactory cytotoxic effect as revealed by the MTT results. Importantly, the highly active complex C4 anticancer effect was compared to the standard chemotherapeutic agents including cisplatin, oxaliplatin and 5-fluorouracil (5-FU). Functionally, C4 suppressed invasion, spheroids formation ability and clonogenic potential of cancer cells. C4 showed synergistic anticancer effect when used in combination with palbociclib, JQ1 and paclitaxel in TNBC cells. Mechanistically, C4 inhibited cyclin-dependent kinase (CDK)4/6 pathway and targeted the expressions of MYC/STAT3/CCND1/CNNE1 axis. Furthermore, C4 suppressed the EMT signaling pathway that suggested a role of C4 in the inhibition of TNBC metastasis. Our findings may pave further in detailed mechanistic study on these complexes as potential chemotherapeutic agents in different types of human cancers.
Assuntos
Antineoplásicos , Ciclina D1 , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Transição Epitelial-Mesenquimal , Fator de Transcrição STAT3 , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Linhagem Celular Tumoral , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Proteínas Proto-Oncogênicas c-myc/metabolismo , Feminino , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Ligantes , Carcinogênese/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Platina/química , Platina/farmacologia , Compostos Organoplatínicos/farmacologia , Compostos Organoplatínicos/química , Compostos Organoplatínicos/síntese químicaRESUMO
Chromosomal translocations of the nucleoporin 98 (NUP98) gene are found in acute myeloid leukemia (AML) patients leading to very poor outcomes. The oncogenic activity of NUP98 fusion proteins is dependent on the interaction between Mixed Lineage Leukemia 1 and menin. NUP98-rearranged (NUP98-r) leukemia cells also rely on specific kinases, including CDK6 and/or FLT3, suggesting that simultaneous targeting of these kinases and menin could overcome limited sensitivity to single agents. Here, we found that combinations of menin inhibitor, MI-3454, with kinase inhibitors targeting either CDK6 (Palbociclib) or FLT3 (Gilteritinib) strongly enhance the anti-leukemic effect of menin inhibition in NUP98-r leukemia models. We found strong synergistic effects of both combinations on cell growth, colony formation and differentiation in patient samples with NUP98 translocations. These combinations also markedly augmented anti-leukemic efficacy of menin inhibitor in Patient Derived Xenograft models of NUP98-r leukemia. Despite inhibiting two unrelated kinases, when Palbociclib or Gilteritinib were combined with the menin inhibitor, they affected similar pathways relevant to leukemogenesis, including cell cycle regulation, cell proliferation and differentiation. This study provides strong rationale for clinical translation of the combination of menin and kinase inhibitors as novel treatments for NUP98-r leukemia, supporting the unexplored combinations of epigenetic drugs with kinase inhibitors.