RESUMEN
BACKGROUND AND OBJECTIVE: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have revolutionised cancer therapy, particularly breast cancer therapy. However, concerns about their potential to cause neurological and psychiatric adverse events (AEs) have emerged, and these concerns remain underexplored. This study aimed to investigate the signals related to neurological and psychiatric AEs associated with CDK4/6 inhibitor use. METHODS: A retrospective study was performed to analyse reports of AEs associated with the use of CDK4/6 inhibitors (abemaciclib, ribociclib and palbociclib) from the first quarter of 2015 to the fourth quarter of 2023 on the basis of the FDA Adverse Event Reporting System (FAERS). Both the reporting odds ratio (ROR) and the multi-item gamma Poisson shrinker (MGPS) were used for signal detection. The timing of events was assessed with the Weibull shape parameter (WSP). The management, analysis and presentation of the data were performed via Python (version 3.8) and R software (version 4.3.2). RESULTS: A total of 19,001 AE reports in which CDK4/6 inhibitors were identified as the 'primary suspect drug' were included in this study. These events were predominantly observed in patients aged 65 to 85 years. Through an ROR analysis, 85 positive signals for neurological and psychiatric AEs associated with CDK4/6 inhibitors were identified. The MGPS method revealed 61 positive AE signals for neurological and psychiatric AEs associated with CDK4/6 inhibitors. A total of 34 positive AE signals were identified by both the ROR and MGPS analyses. The WSP indicated that the onset times for AEs associated with all three CDK4/6 inhibitors tended to be early in drug therapy, suggesting a propensity for early failure type. CONCLUSION: The present study revealed neurological and psychiatric AEs associated with CDK4/6 inhibitors that often occur early in treatment. Significant signals include spinal cord herniation and cerebral microangiopathy. Close monitoring of these AEs is crucial. Further studies are necessary to verify the connection between CDK4/6 inhibitors and neurological and psychiatric AEs.
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Sistemas de Registro de Reacción Adversa a Medicamentos , Neoplasias de la Mama , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Farmacovigilancia , Inhibidores de Proteínas Quinasas , United States Food and Drug Administration , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Estados Unidos/epidemiología , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Sistemas de Registro de Reacción Adversa a Medicamentos/estadística & datos numéricos , Estudios Retrospectivos , Inhibidores de Proteínas Quinasas/efectos adversos , Persona de Mediana Edad , Anciano , Adulto , Trastornos Mentales/inducido químicamente , Trastornos Mentales/tratamiento farmacológico , Enfermedades del Sistema Nervioso/inducido químicamente , Piperazinas/efectos adversos , Antineoplásicos/efectos adversos , Piridinas/efectos adversos , Anciano de 80 o más Años , Aminopiridinas/efectos adversos , Purinas/efectos adversosRESUMEN
Mammalian cells make the decision to divide at the G1-S transition in response to diverse signals impinging on the retinoblastoma protein Rb, a cell cycle inhibitor and tumor suppressor. Passage through the G1-S transition is initially driven by Rb inactivation via phosphorylation and by Rb's decreasing concentration in G1. While many studies have identified the mechanisms of Rb phosphorylation, the mechanism underlying Rb's decreasing concentration in G1 was unknown. Here, we found that Rb's concentration decrease in G1 requires the E3 ubiquitin ligase UBR5. UBR5 knockout cells have increased Rb concentration in early G1, exhibited a lower G1-S transition rate, and are more sensitive to inhibition of cyclin-dependent kinase 4/6 (Cdk4/6). This last observation suggests that UBR5 inhibition can strengthen the efficacy of Cdk4/6 inhibitor-based cancer therapies.
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Quinasa 4 Dependiente de la Ciclina , Proteína de Retinoblastoma , Ubiquitina-Proteína Ligasas , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Humanos , Proteína de Retinoblastoma/metabolismo , Proteína de Retinoblastoma/genética , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/genética , Proteolisis , Fase G1 , Fase S , Fosforilación , Línea Celular TumoralRESUMEN
BACKGROUND: Currently, the combination of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and endocrine therapy is a first-line treatment for hormone-receptor-positive and HER2-negative metastatic breast cancer. This study aimed to assess the impact of changes in Mean Corpuscular Volume (MCV) on predicting responses to treatment and survival in patients with hormone-receptor-positive, HER2-negative metastatic breast cancer receiving CDK4/6 inhibitors and endocrine therapy. METHODS: Retrospectively, data on hemoglobin levels, MCV, B12, folate levels, and survival times were collected from 275 patients. Patients were categorized into two groups based on the degree of MCV change (delta MCV ≤ 10 vs. >10). Kaplan-Meier survival analysis was performed, with significance set at p < 0.05. RESULTS: The average age of the patients was 56.1 ± 12.1 years. In total, 72.7% received CDK4/6 inhibitors as first-line treatment, while 27.3% received them as second-line treatment. Before CDK4/6 inhibitor use, the median MCV level was 87.7 fL (IQR: 83-91), which increased to 98 fL (IQR: 92-103) after treatment (p < 0.001). ECOG performance score, CDK4/6 inhibitor treatment line, type of endocrine therapy, and MCV change were identified as independent predictors of progression-free survival in the Cox regression model. The median progression-free survival for the entire group was 28 months. Patients with MCV delta > 10 had a median progression-free survival of 33 months, compared to 23 months for those with MCV delta ≤ 10 (p = 0.029). There was no significant difference in median overall survival times between the two groups (p = 0.158). CONCLUSION: This study highlights that patients with MCV delta > 10 had longer median progression-free survival compared to those with MCV delta ≤ 10.
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Neoplasias de la Mama , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Índices de Eritrocitos , Inhibidores de Proteínas Quinasas , Humanos , Persona de Mediana Edad , Femenino , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Estudios Retrospectivos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/sangre , Anciano , AdultoRESUMEN
One of the main regulators in the cell cycle is cyclin-dependent kinase 4 and 6 (CDK4/6). FDA has approved CDK4/6 inhibitors for the treatment of patients with metastatic breast cancer. However, the development of selective agents remains problematic due to the conservation of their ATP binding sites. In the previous in silico study, ZINC585292724, ZINC585292587, ZINC585291674, and ZINC585291474 have been identified as potential inhibitors. Therefore, the present study aimed to analyze the selectivity and inhibitory activity of the four compounds against CDK4/6 in vitro as well as determine the potential for their further development in silico. The in vitro results showed that the four compounds had good selectivity towards both kinases, due to their similar structure. In agreement with the in silico results, ZINC585291674 produced the best inhibitory activity against CDK4 and CDK6, with IC50 of 184.14 nM and 111.78 nM, respectively. Their ADMET profile were also similar to reference compound of Palbociclib. Based on this, ZINC585291674 can be used as a lead compound for further inhibitor development.
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Simulación por Computador , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Inhibidores de Proteínas Quinasas , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/metabolismo , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/metabolismo , Humanos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Simulación del Acoplamiento Molecular , Piperazinas/farmacología , Piperazinas/química , Antineoplásicos/farmacología , Antineoplásicos/química , Piridinas/farmacología , Piridinas/químicaRESUMEN
OBJECTIVE: This study used real-world observational data to compare profiles of patients receiving different first-line treatment for hormone receptor positive (ER+), HER2 negative, metastatic breast cancer (MBC): CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) versus ET alone. METHOD: From a nationwide electronic health record-derived Flatiron Health de-identified database including 280 US cancer clinics, we identified patients with hormone receptor positive, HER2 negative, metastatic breast cancer receiving 1st -line therapy with ET alone or CDK4/6i plus ET between February 2015 and November 2021. Patient sociodemographic status, MBC treatment regimen and outcomes were the focus of this analysis. Patient characteristics were compared using t-tests and chi-square tests. Logistic regression analysis was performed to examine the association of patient characteristics with the likelihood of receiving 1st -line CDK4/6i plus ET vs. ET alone. Kaplan-Meier method and Cox proportional hazards were used to test the impact of 1st -line treatment regimen on real-world progression-free survival (PFS) and overall survival (OS). Baseline characteristics were balanced using inverse probability weighting (IPW). RESULTS: The study population included 3,917 patients receiving CDK4/6i plus ET (n = 2170) and ET alone (n = 1747) for their MBC. Compared to patients receiving ET alone, those receiving CDK4/6i plus ET were younger (mean age 66.8 vs. 68.6, p < 0.001), more likely to present with de novo MBC (p < 0.001), had better performance status (50.2% vs. 40.5% patients with ECOG value 0, p = 0.001) and lower number of comorbidities (29.7% vs. 26.6% ≥ 1 comorbidity, p < 0.001). Logistic regression revealed increased odds of CDK4/6i plus ET in individuals aged 50-64 (OR: 3.42, 95% CI [2.41, 4.86]) and 65-74 (OR: 3.18, 95% CI [1.68, 6.02]) versus those aged 18-49 years of age. Black individuals had lower odds of CDK4/6i plus ET (OR: 0.76, 95% CI [0.58, 1.00]) compared to White individuals. Other characteristics associated with lower odds of CDK4/6i plus ET included patients with stage III disease (OR: 0.69, 95% CI [0.52, 0.92]), lower performance status (OR: 0.50, 95% CI [0.40, 0.62]), and Medicare insurance (OR: 0.73, 95% CI [0.30, 1.78]) compared to those with commercial and Medicaid insurance. After IPW adjustment, use of CDK4/6i plus ET as 1st -line treatment was associated with significantly longer median PFS compared to ET alone (27 vs. 17 months; hazard ratio [HR] = 0.61, p < 0.001). Median OS was 52 months in the CDK4/6i plus ET group and was 42 months with ET alone (HR = 0.74, p < 0.001). CONCLUSION: In this real-world database, disparities in receiving 1st -line CDK4/6 inhibitors were seen by age, diagnosis stage, baseline performance status, comorbidity, and insurance status. In adjusted analysis, the use of 1st -line CDK4/6i plus ET yielded better PFS and OS rates than ET alone. Further efforts are essential to enhance equitable use of and access to this crucial drug class.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Inhibidores de Proteínas Quinasas , Receptor ErbB-2 , Receptores de Estrógenos , Receptores de Progesterona , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/metabolismo , Receptor ErbB-2/metabolismo , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Persona de Mediana Edad , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Anciano , Inhibidores de Proteínas Quinasas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Adulto , Disparidades en Atención de Salud , Antineoplásicos Hormonales/uso terapéutico , Metástasis de la NeoplasiaRESUMEN
Therapeutic drug monitoring (TDM) may be beneficial for cyclin-dependent kinase 4/6 inhibitors (CDK4/6is), such as palbociclib, ribociclib, and abemaciclib, due to established exposure-toxicity relationships and the potential for monitoring treatment adherence. Developing a method for quantifying CDK4/6is, abemaciclib metabolites (M2, M20), and letrozole in dried blood spots (DBS) could be useful to enhance the feasibility of TDM. Thus, an optimized LC-MS/MS method was developed using the HemaXis DB10 device for volumetric (10 µL) DBS collection. Chromatographic separation was achieved using a reversed-phase XBridge BEH C18 column. Detection was performed with a triple quadrupole mass spectrometer, utilizing ESI source switching between negative and positive ionization modes and multiple reaction monitoring acquisition. Analytical validation followed FDA, EMA, and IATDMCT guidelines, demonstrating high selectivity, adequate sensitivity (LLOQ S/N ≥ 30), and linearity (r ≥ 0.997). Accuracy and precision met acceptance criteria (between-run: accuracy 95-106%, CV ≤ 10.6%). Haematocrit independence was confirmed (22-55%),with high recovery rates (81-93%) and minimal matrix effects (ME 0.9-1.1%). The stability of analytes under home-sampling conditions was also verified. Clinical validation supports DBS-based TDM as feasible, with conversion models developed for estimating plasma concentrations (the reference for TDM target values) of letrozole, abemaciclib, and its metabolites. Preliminary data for palbociclib and ribociclib are also presented.
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Aminopiridinas , Bencimidazoles , Pruebas con Sangre Seca , Monitoreo de Drogas , Letrozol , Piperazinas , Purinas , Piridinas , Espectrometría de Masas en Tándem , Piperazinas/sangre , Piridinas/sangre , Espectrometría de Masas en Tándem/métodos , Humanos , Monitoreo de Drogas/métodos , Purinas/sangre , Letrozol/sangre , Bencimidazoles/sangre , Aminopiridinas/sangre , Pruebas con Sangre Seca/métodos , Cromatografía Liquida/métodos , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/sangre , Cromatografía Líquida con Espectrometría de MasasRESUMEN
PURPOSE: The optimal treatment sequence for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) after progression on first-line cyclin-dependent kinase 4/6 inhibitor (CDKi) and endocrine therapy is unclear. Clinical and biological factors influencing treatment choices and outcomes in the second-line setting need to be elucidated. MATERIALS AND METHODS: This is a retrospective analysis of a real-world cohort including patients with HR+/HER2- ABC who received CDKi and endocrine therapy in the first-line setting and progressed, requiring second-line treatment. Clinical and biological factors were analyzed to evaluate their association with daily treatment decisions and the prognostic role of progression-free survival (PFS) in the second-line setting. RESULTS: Two hundred thirty-five patients were included. Second-line treatments were hormone therapy (HT) based in 60% and chemotherapy based in 40% of patients. The second-line median PFS was 6.6 months, with no difference between treatment types. In multivariable analysis, postmenopausal status, lower Ki-67 expression, and non-de novo stage IV disease were associated with improved second-line (2L) PFS. Menopausal status significantly interacted with treatment type, with reduced PFS in premenopausal patients receiving HT-based treatments (4.7 v 8.7 months, P = .00045). CONCLUSION: In our study, treatment decisions reflected the current algorithm incorporated in our clinical guidelines, and prior treatment response was the most relevant factor to determine 2L treatment decision. Menopausal status interacted with the subsequent therapy efficacy in this setting. Hence, we consider that menopausal status should be routinely evaluated in the subgroup analysis of clinical trials.
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Neoplasias de la Mama , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Inhibidores de Proteínas Quinasas , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Persona de Mediana Edad , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Estudios Retrospectivos , Argentina/epidemiología , Anciano , Adulto , Inhibidores de Proteínas Quinasas/uso terapéutico , Anciano de 80 o más Años , Receptor ErbB-2/metabolismo , Supervivencia sin ProgresiónRESUMEN
The therapeutic landscape for hormone receptor-positive (HR+) breast carcinoma has undergone a significant transformation with the advent of cyclin-dependent kinase (CDK)4/6 inhibitors, particularly in combination with endocrine therapy as the primary regimen. However, the evolution of resistance mechanisms in response to CDK4/6 inhibitors in HR+ metastatic breast cancer presents substantial challenges in managing the disease. This review explores the diverse genomic landscape underlying resistance, including disturbances in the cell cycle, deviations in oncogenic signaling pathways, deficiencies in DNA damage response (DDR) mechanisms, and changes in the tumor microenvironment (TME). Additionally, it discusses potential strategies to surmount resistance, including advancements in endocrine therapy, targeted inhibition of cell cycle components, suppression of AKT/mTOR activation, exploration of the FGFR pathway, utilization of antibody-drug conjugates (ADCs), and integration of immune checkpoint inhibitors (ICIs) with endocrine therapy and CDK4/6 inhibitors, providing pathways for enhancing patient outcomes amidst treatment challenges.
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Neoplasias de la Mama , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Resistencia a Antineoplásicos , Inhibidores de Proteínas Quinasas , Microambiente Tumoral , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Femenino , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Transducción de Señal/efectos de los fármacos , Receptores de Estrógenos/metabolismoRESUMEN
BACKGROUND: Cyclin-dependent kinases (CDK) 4/6 inhibitors have significantly improved outcomes for patients with ER+/HER2- breast cancer. Nevertheless, they differ from each other in terms of chemical, biological, and pharmacological features, as well as toxicity profiles. We aim to determine whether QTc prolongation is caused by CDK4/6i in general or if it is associated with ribociclib only. METHODS: We systematically searched PubMed, Embase, and Cochrane Library for randomized controlled trials (RCTs) comparing the prevalence of QTc prolongation as an adverse event in HR+ breast cancer patients treated with CDK4/6i vs those without CDK4/6i. We pooled relative risk (RR) and mean difference (MD) with 95% confidence interval (CI) for the binary endpoint of QT prolongation. RESULTS: We included 14 RCTs comprising 16â196 patients, of whom 8576 underwent therapy with CDK4/6i. An increased risk of QTc prolongation was associated with the use of CDK4/6i (RR = 2.35, 95% CI = 1.67 to 3.29, P < .001; I2 = 44%). Subgroup analyses revealed a significant increase in the QTc interval for the ribociclib and palbociclib cohorts. The ribociclib subgroup showed a relative risk of 3.12 (95% CI = 2.09 to 4.65, P < .001; I2 = 12%), whereas the palbociclib subgroup had a relative risk of 1.51 (95% CI = 1.05 to 2.15, P = .025; I2 = 0%). CONCLUSION: Palbociclib was associated with QTc prolongation; however, the relative risk for any grade QTc was quantitively twice with ribociclib. Furthermore, grade 3 QTc prolongations were observed exclusively with ribociclib. These results are important for guiding clinical decision-making and provide reassurance regarding the overall safety profile of this drug class.
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Aminopiridinas , Neoplasias de la Mama , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Síndrome de QT Prolongado , Piperazinas , Inhibidores de Proteínas Quinasas , Purinas , Piridinas , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Purinas/efectos adversos , Purinas/uso terapéutico , Purinas/administración & dosificación , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Síndrome de QT Prolongado/inducido químicamente , Aminopiridinas/efectos adversos , Aminopiridinas/uso terapéutico , Aminopiridinas/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Piperazinas/efectos adversos , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/administración & dosificación , Piridinas/efectos adversos , Piridinas/uso terapéutico , Piridinas/administración & dosificación , Femenino , Roscovitina/efectos adversos , BencimidazolesRESUMEN
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, Ras-driven sarcomas characterized by loss of the NF1 tumor suppressor gene and hyperactivation of MEK and CDK4/6 kinases. MPNSTs lack effective therapies. We recently demonstrated remarkable efficacy of dual CDK4/6-MEK inhibition in mice with de novo MPNSTs, which was heightened by combined targeting of the immune checkpoint protein, PD-L1. The triple combination therapy targeting CDK4/6, MEK, and PD-L1 led to extended MPNST regression and improved survival, although most tumors eventually acquired drug resistance. Here, we consider the immune activation phenotype caused by CDK4/6-MEK inhibition in MPNSTs that uniquely involved intratumoral plasma cell accumulation. We discuss how PD-L1 and FOXM1, a tumor-promoting transcription factor, are functionally linked and may be key mediators of resistance to CDK4/6-MEK targeted therapies. Finally, the role of FOXM1 in suppressing anti-tumor immunity and potentially thwarting immune-based therapies is considered. We suggest that future therapeutic strategies targeting the oncogenic network of CDK4/6, MEK, PD-L1, and FOXM1 represent exciting future treatment options for MPNST patients.
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Antígeno B7-H1 , Quinasa 4 Dependiente de la Ciclina , Resistencia a Antineoplásicos , Proteína Forkhead Box M1 , Proteína Forkhead Box M1/metabolismo , Proteína Forkhead Box M1/genética , Humanos , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/metabolismo , Animales , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Ratones , Terapia Molecular Dirigida , Neurofibrosarcoma/metabolismo , Neurofibrosarcoma/tratamiento farmacológico , Neurofibrosarcoma/patología , Neurofibrosarcoma/genética , Neoplasias de la Vaina del Nervio/tratamiento farmacológico , Neoplasias de la Vaina del Nervio/metabolismo , Neoplasias de la Vaina del Nervio/patología , Neoplasias de la Vaina del Nervio/genética , Neoplasias de la Vaina del Nervio/inmunologíaRESUMEN
BACKGROUND: Cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors have emerged as a significant advancement in the treatment of HR+/HER2- metastatic breast cancer (MBC). Despite the clinical efficacy of CDK 4/6 inhibitors in HR+/HER2- metastatic breast cancer, there remains a significant gap in understanding their cost-effectiveness, particularly regarding the long-term economic impact and the key drivers of costs, when used in combination with endocrine therapy. This study aims to systematically review and conduct a meta-analysis of cost-effectiveness studies evaluating CDK4/6 inhibitors in treatment of HR+/HER2- advanced breast cancer and identify key drivers of costs of CDK4/6 inhibitors in combination with endocrine therapy. METHODS: A comprehensive search of PubMed and Embase was conducted to identify peer-reviewed studies from February 2015 to March 2022 reporting cost-effectiveness of CDK4/6 inhibitors in MBC treatment. Incremental net benefits (INBs) were estimated, and meta-analysis was conducted. This review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: We identified 120 articles, of which 18 were eligible for systematic review and 16 for meta-analysis. None of the three CDK4/6 inhibitors had positive INB compared to endocrine/aromatase inhibitors therapy alone. The pooled INB was estimated at -$149,266.87 (95% Confidence Interval (CI) = -$196,961.54, -$101,572.20). CONCLUSION: The combination of CDK4/6 inhibitors and letrozole/endocrine therapy for the treatment of postmenopausal patients with advanced HR+/HER2 - MBC was not cost-effective.
Breast cancer, a significant health concern worldwide, represents around 30% of new cancer diagnoses and 25% of cancer related fatalities. Among these cases, approximately two-thirds are characterized by hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) tumors. In the metastatic stage, up to half of patients exhibit inherent resistance to endocrine therapy, leading to poorer survival rates, while others, initially responsive, eventually develop resistance, leading to disease progression and eventual mortality. Nevertheless, recent advancements in CDK4/6 inhibitors have shown efficacy in overcoming both inherent and acquired endocrine resistance, representing a substantial breakthrough in HR+/HER2− metastatic breast cancer treatment. This study conducts a review of literature focusing on comparative cost-effectiveness and economic evaluations of the three CDK4/6 inhibitors, evaluating the pooled incremental net benefit (INB) reported in these studies. It marks the first attempt to compare all three CDK4/6 inhibitors and employs a meta-analysis approach to ascertain the option demonstrating the most positive INB. Our findings indicate that CDK4/6 inhibitors fail to provide an economic advantage over letrozole or endocrine therapy alone. The aim of this study is to offer insights for clinical and reimbursement decision-making in the treatment of postmenopausal patients with advanced HR+/HER2− breast cancer, providing valuable guidance for policymakers, payers, and clinicians.
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Neoplasias de la Mama , Análisis Costo-Beneficio , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Inhibidores de Proteínas Quinasas , Receptor ErbB-2 , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/economía , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Femenino , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Receptor ErbB-2/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/economía , Inhibidores de Proteínas Quinasas/uso terapéutico , Metástasis de la Neoplasia , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Aminopiridinas , Piperazinas , Purinas , PiridinasAsunto(s)
Enfermedades Autoinmunes , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Inhibidores de Proteínas Quinasas , Humanos , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Enfermedades Autoinmunes/tratamiento farmacológico , Femenino , Neoplasias/tratamiento farmacológico , Masculino , Anciano , Enfermedades Cutáneas Vesiculoampollosas/tratamiento farmacológico , Enfermedades Cutáneas Vesiculoampollosas/patología , Persona de Mediana Edad , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos , Piperazinas/uso terapéutico , Piperazinas/efectos adversos , Comités Consultivos , Estudios de Cohortes , PiridinasRESUMEN
BACKGROUND: Recently, cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have emerged as a novel treatment strategy for breast cancer. However, increasing reports of CDK4/6i-associated venous thromboembolism (VTE) have garnered attention. This study assessed CDK4/6i-associated VTE in breast cancer, and examined the effect of CDK4/6i on platelet/coagulation function for the first time in vitro. METHODS: PubMed and Embase databases were searched for studies published from the establishment of the database to December 31, 2022 for randomized controlled trials (RCTs) and real-world studies of CDK4/6i in patients with breast cancer, and the data obtained from the included studies were used for meta-analysis. A disproportionality analysis by extracting adverse drug reaction signals of CDK4/6i-associated VTE from the FDA Adverse Event Reporting System (FAERS) database was also conducted. Additionally, the in vitro effect of CDK4/6i on platelet function was assessed based on platelet aggregation tests and flow cytometry, and coagulation function was assessed based on the blood clotting function test. FINDINGS: A total of 16,903 patients in 13 RCTs and 6,490 patients in 9 real-world studies were included in the meta-analysis. In RCTs, VTE occurred in 193 (2.1 %) and 55 (0.7 %) patients in the CDK4/6i and control groups, respectively. In real-world studies, the aggregate incidence rate of VTE was 4.2 % (95 % CI: 2.1, 6.3). The meta-analysis of RCTs revealed that abemaciclib (Odds ratio [OR]: 4.40 [95 % CI: 2.74,7.05], p < 0.001) and palbociclib (OR: 2.35 [95 % CI: 1.34, 4.12], p < 0.01) significantly increased the risk of VTE in patients with breast cancer compared to placebo. FAERS database analysis revealed that abemaciclib (reporting odds ratio [ROR]: 1.63 [95 % CI: 1.36, 1.97]; IC025: 0.67) and ribociclib (ROR: 1.17 [95 % CI: 1.0, 1.39]; IC025: 0.18) demonstrated a significantly increased signal of VTE. Similarly, findings from in vitro experiments demonstrated that abemaciclib enhanced agonist-induced platelet activation, especially when collagen was used as the inducer, and this effect became more prominent with increasing its concentration. INTERPRETATION: Use of abemaciclib may increase the risk of VTE in patients with breast cancer, which may be partially attributed to the effect of abemaciclib on platelet function. Close monitoring of VTE occurrence is highly recommended while using abemaciclib, especially in patients at a high risk of VTE.
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Aminopiridinas , Bencimidazoles , Neoplasias de la Mama , Farmacovigilancia , Tromboembolia Venosa , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Tromboembolia Venosa/inducido químicamente , Tromboembolia Venosa/epidemiología , Bencimidazoles/efectos adversos , Bencimidazoles/uso terapéutico , Femenino , Aminopiridinas/efectos adversos , Aminopiridinas/uso terapéutico , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Bases de Datos Factuales , Inhibidores de Proteínas Quinasas/efectos adversos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Luminal Androgen Receptor (LAR) triple-negative breast cancers (TNBC) express androgen receptors (AR), exhibit high frequency of PIK3CA mutations and intact RB. Herein, we investigated combined blockade of the CDK4/6 and PI3K signaling with palbociclib, alpelisib, and capivasertib, which inhibit CDK4/6, PI3Kα, and AKT1-3, respectively. The combination of palbociclib/capivasertib, but not palbociclib/alpelisib, synergistically inhibited proliferation of MDA-MB-453 and MFM-223 LAR cells [synergy score 7.34 (p = 5.81x10-11) and 4.78 (p = 0.012), respectively]. The AR antagonist enzalutamide was inactive against MDA-MB-453, MFM-223, and CAL148 cells and did not enhance the efficacy of either combination. Palbociclib/capivasertib inhibited growth of LAR patient-derived xenografts more potently than palbociclib/alpelisib. Treatment of LAR cells with palbociclib suppressed phosphorylated-RB and resulted in adaptive phosphorylation/activation of S473 pAKT and AKT substrates GSK3ß, PRAS40, and FoxO3a. Capivasertib blocked palbociclib-induced phosphorylation of AKT substrates more potently than alpelisib. Treatment with PI3Kß inhibitors did not block phosphorylation of AKT substrates, suggesting that PI3Kß did not mediate the adaptive response to CDK4/6 inhibition. Phosphokinase arrays of MDA-MB-453 cells treated with palbociclib showed time-dependent upregulation of PDGFRß, GSK3ß, STAT3, and STAT6. RNA silencing of PDGFRß in palbociclib-treated MDA-MB-453 and MFM-223 cells blocked the upregulation of S473 pAKT, suggesting that the adaptive response to CDK4/6 blockade involves PDGFRß signaling. Finally, treatment with palbociclib and the PDGFR inhibitor CP637451 arrested growth of MDA-MB-453 and MFM-223 cells to the same degree as palbociclib/capivasertib. These findings support testing the combination of CDK4/6 and AKT inhibitors in patients with LAR TNBC, and further investigation of PDGFR antagonists in this breast cancer subtype.
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Protocolos de Quimioterapia Combinada Antineoplásica , Proliferación Celular , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Piperazinas , Proteínas Proto-Oncogénicas c-akt , Piridinas , Receptores Androgénicos , Neoplasias de la Mama Triple Negativas , Ensayos Antitumor por Modelo de Xenoinjerto , Humanos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/metabolismo , Piperazinas/farmacología , Animales , Femenino , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/metabolismo , Piridinas/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Línea Celular Tumoral , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/metabolismo , Receptores Androgénicos/metabolismo , Receptores Androgénicos/genética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Proliferación Celular/efectos de los fármacos , Ratones , Pirimidinas/farmacología , Sinergismo Farmacológico , Transducción de Señal/efectos de los fármacos , Feniltiohidantoína/farmacología , Feniltiohidantoína/análogos & derivados , Benzamidas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Nitrilos/farmacología , Pirroles/farmacología , TiazolesRESUMEN
Progression of cystic kidney disease has been linked to activation of the mTORC1 signaling pathway. Yet the utility of mTORC1 inhibitors to treat patients with polycystic kidney disease remains controversial despite promising preclinical data. To define the cell intrinsic role of mTORC1 for cyst development, the mTORC1 subunit gene Raptor was selectively inactivated in kidney tubular cells lacking cilia due to simultaneous deletion of the kinesin family member gene Kif3A. In contrast to a rapid onset of cyst formation and kidney failure in mice with defective ciliogenesis, both kidney function, cyst formation discerned by magnetic resonance imaging and overall survival were strikingly improved in mice additionally lacking Raptor. However, these mice eventually succumbed to cystic kidney disease despite mTORC1 inactivation. In-depth transcriptome analysis revealed the rapid activation of other growth-promoting signaling pathways, overriding the effects of mTORC1 deletion and identified cyclin-dependent kinase (CDK) 4 as an alternate driver of cyst growth. Additional inhibition of CDK4-dependent signaling by the CDK4/6 inhibitor Palbociclib markedly slowed disease progression in mice and human organoid models of polycystic kidney disease and potentiated the effects of mTORC1 deletion/inhibition. Our findings indicate that cystic kidneys rapidly adopt bypass mechanisms typically observed in drug resistant cancers. Thus, future clinical trials need to consider combinatorial or sequential therapies to improve therapeutic efficacy in patients with cystic kidney disease.
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Quinasa 4 Dependiente de la Ciclina , Cinesinas , Diana Mecanicista del Complejo 1 de la Rapamicina , Transducción de Señal , Animales , Humanos , Ratones , Cilios/patología , Cilios/metabolismo , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 4 Dependiente de la Ciclina/genética , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Enfermedades Renales Quísticas/genética , Enfermedades Renales Quísticas/metabolismo , Enfermedades Renales Quísticas/patología , Enfermedades Renales Quísticas/tratamiento farmacológico , Cinesinas/genética , Cinesinas/metabolismo , Cinesinas/antagonistas & inhibidores , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Ratones Noqueados , Piperazinas/farmacología , Piperazinas/uso terapéutico , Enfermedades Renales Poliquísticas/genética , Enfermedades Renales Poliquísticas/metabolismo , Enfermedades Renales Poliquísticas/patología , Enfermedades Renales Poliquísticas/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/farmacología , Piridinas/uso terapéuticoRESUMEN
PURPOSE: The National Cancer Institute-Children's Oncology Group Pediatric Molecular Analysis for Therapy Choice trial assigned patients age 1-21 years with relapsed or refractory solid tumors, lymphomas, and histiocytic disorders to phase II treatment arms of molecularly targeted therapies on the basis of genetic alterations detected in their tumor. Patients with tumors that harbored prespecified genomic alterations in the cyclinD-CDK4/6-INK4a-Rb pathway with intact Rb expression were assigned and treated with the cdk4/6 inhibitor palbociclib. METHODS: Patients received palbociclib orally once daily for 21 days of 28-day cycles until disease progression, intolerable toxicity, or up to 2 years. The primary end point was objective response rate; secondary end points included safety/tolerability and progression-free survival. RESULTS: Twenty-three patients (median age, 15 years; range, 8-21) were enrolled; 20 received protocol therapy and were evaluable for toxicity and response. Of the evaluable patients, the most common diagnoses were osteosarcoma (n = 9) and rhabdomyosarcoma (n = 6). A single actionable gene amplification was found in 19 tumors (CDK4, n = 11, CDK6, n = 2, CCND3, n = 6), with one tumor harboring two amplifications (CDK4 and CCND2). Hematologic toxicities were the most common treatment-related events. No objective responses were seen. Two patients with tumors harboring CDK4 amplifications (neuroblastoma and sarcoma) had best response of stable disease for six and three cycles. Six-month progression was 10% (95% CI, 1.7 to 27.2). CONCLUSION: The CDK4/6 inhibitor palbociclib at 75 mg/m2 orally daily was tolerable in this heavily pretreated cohort. No objective responses were observed in this histology-agnostic biomarker-selected population with treatment-refractory solid tumors, demonstrating that pathway alteration alone is insufficient in pediatric cancers to generate a response to palbociclib monotherapy.
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Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Neoplasias , Piperazinas , Piridinas , Humanos , Piridinas/uso terapéutico , Piperazinas/uso terapéutico , Niño , Adolescente , Femenino , Masculino , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/genética , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Adulto Joven , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/genética , Preescolar , Ciclina D/genéticaRESUMEN
BACKGROUND: In luminal breast cancer, adjuvant CDK4/6 inhibitors (eg, abemaciclib) improve invasive disease-free survival. In patients with T1-2, grade 1-2 tumours, and one or two sentinel lymph node metastases, completion axillary lymph node dissection (cALND) is the only prognostic tool available that can reveal four or more nodal metastases (pN2-3), which is the only indication for adjuvant abemaciclib in this setting. However, this technique can lead to substantial arm morbidity in patients. We aimed to pragmatically describe the potential benefit and harm of this strategy on the individual patient level in patients from the ongoing SENOMAC trial. METHODS: In the randomised, phase 3, SENOMAC trial, patients aged 18 years or older, of any performance status, with clinically node-negative T1-T3 breast cancer and one or two sentinel node macrometastases from 67 sites in five European countries (Denmark, Germany, Greece, Italy, and Sweden) were randomly assigned (1:1), via permutated block randomisation (random block size of 2 and 4) stratified by country, to either cALND or its omission (ie, they had a sentinel lymph node biopsy only). The primary outcome is overall survival, which is yet to be reported. In this post-hoc analysis, patients from the SENOMAC per-protocol population, with luminal oestrogen-receptor positive, HER2-negative, T1-2, histological grade 1-2 breast cancer, with tumour size of 5 cm or smaller were selected to match the characteristics of cohort 1 of the monarchE trial who would only have an indication for adjuvant abemaciclib if found to have 4 or more nodal metastases. The primary study objective was to determine the number of patients who developed patient-reported severe or very severe impairment of physical arm function after cALND (as measured by the Lymphedema Functioning, Disability, and Health [Lymph-ICF] Questionnaire) 1 year after surgery to avoid one invasive disease-free survival event at 5 years with 2 years of adjuvant abemaciclib, using invasive disease-free survival event data from cohort 1 of the monarchE trial. The SENOMAC trial is registered with ClincialTrials.gov, NCT02240472, and is closed to accrual and ongoing. FINDINGS: Between Jan 31, 2015, and Dec 31, 2021, 2766 patients were enrolled in SENOMAC and randomly assigned to cALND (n=1384) or sentinel node biopsy only (n=1382), of whom 2540 were included in the per-protocol population. 1705 (67%) of 2540 patients met this post-hoc study's eligibility criteria, of whom 802 (47%) had a cALND and 903 (53%) had a sentinel lymph node biopsy only. Median age at randomisation was 62 years (IQR 52-71), 1699 (>99%) of 1705 patients were female, and six (<1%) were male. Among 1342 patients who responded to questionnaires, after a median follow-up of 45·2 months (IQR 25·6-59·8; data cutoff Nov 17, 2023), patient-reported severe or very severe impairment of physical arm function was reported in 84 (13%) of 634 patients who had cALND versus 30 (4%) of 708 who had sentinel lymph node biopsy only (χ2 test p<0·0001). To avoid one invasive disease-free survival event at 5 years with adjuvant abemaciclib, cALND would need to be performed in 104 patients, and would result in nine patients having severe or very severe impairment of physical arm function 1 year after surgery. INTERPRETATION: As a method to potentially identify an indication for abemaciclib, and subsequently avoid invasive disease-free survival events at 5 years with 2 years of adjuvant abemaciclib, cALND carries a substantial risk of severe or very severe arm morbidity and so cALND should be discouraged for this purpose. FUNDING: Swedish Research Council, the Swedish Cancer Society, the Nordic Cancer Union, and the Swedish Breast Cancer Association.
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Neoplasias de la Mama , Escisión del Ganglio Linfático , Metástasis Linfática , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Femenino , Persona de Mediana Edad , Anciano , Quimioterapia Adyuvante , Axila , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Adulto , Aminopiridinas/uso terapéutico , Estadificación de Neoplasias , Inhibidores de Proteínas Quinasas/uso terapéutico , Supervivencia sin Enfermedad , BencimidazolesRESUMEN
OBJECTIVES: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have significantly improved the survival of patients with hormone receptor-positive HER2-negative advanced breast cancer (ABC). Although stereotactic ablative radiotherapy (SABR) is used more often in routine clinical practice, data on the safety and efficacy of combining SABR with CDK4/6i are lacking. Herein, we present the results of SABR combined with CDK4/6i in ABC. METHODS: Patients with ABC who received CDK4/6i and SABR between 2018 and 2023 were analysed. RESULTS: Among 384 patients treated with CDK4/6i, 34 patients received 44 courses of SABR. Two-year progression-free survival (PFS) was 63.6% (95% CI, 45.8-88.3), and the median PFS was 32 months. Three-year overall survival (OS) was 88.9% (95% CI, 77.7-100). Two-year local control (LC) was 92.7% (95% CI, 83.4-100). Median OS and LC were not reached. The subgroup analysis showed the difference in survival between oligometastatic patients (OMD) and non-OMD subgroup. Two-year PFS was 69.2% (95% CI, 44.5-100) in OMD compared with 57.4% (95% CI, 36-91.7) in the non-OMD (P = .042). Three-year OS was 90% (95% CI, 73.2-100) in OMD compared with 86.2% (95% CI, 70-100) in the non-OMD (P = .67). Median PFS and OS in the non-OMD were 26 and 56 months, respectively, and were not reached in OMD. Fifteen patients required CDK4/6i dose reduction, and 2 discontinued treatment due to toxicity. No difference in high-grade toxicity was observed between the sequential and concurrent SABR. CONCLUSION: The addition of SABR to CDK4/6i seems to be safe and effective, especially in patients with oligometastatic disease. ADVANCES IN KNOWLEDGE: In advanced breast cancer patients treated with CDK4/6i, SABR provides a high local control and may provide additional benefit in an oligometastatic setting.
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Neoplasias de la Mama , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Radiocirugia , Humanos , Neoplasias de la Mama/radioterapia , Neoplasias de la Mama/patología , Femenino , Radiocirugia/métodos , Persona de Mediana Edad , Anciano , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Adulto , Anciano de 80 o más Años , Receptor ErbB-2/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Terapia Combinada , Estudios Retrospectivos , Supervivencia sin Progresión , Metástasis de la NeoplasiaRESUMEN
Several FDA-approved adjuvants signal through the NLRP3 inflammasome and IL-1ß release. Identifying small molecules that induce IL-1ß release could allow targeted delivery and structure-function optimization, thereby improving safety and efficacy of next-generation adjuvants. In this work, we leverage our existing high throughput data set to identify small molecules that induce IL-1ß release. We find that ribociclib induces IL-1ß release when coadministered with a TLR4 agonist in an NLRP3- and caspase-dependent fashion. Ribociclib was formulated with a TLR4 agonist into liposomes, which were used as an adjuvant in an ovalbumin prophylactic vaccine model. The liposomes induced antigen-specific immunity in an IL-1 receptor-dependent fashion. Furthermore, the liposomes were coadministered with a tumor antigen and used in a therapeutic cancer vaccine, where they facilitated rejection of E.G7-OVA tumors. While further chemical optimization of the ribociclib scaffold is needed, this study provides proof-of-concept for its use as an IL-1 producing adjuvant in various immunotherapeutic contexts.
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Quinasa 4 Dependiente de la Ciclina , Inflamasomas , Interleucina-1beta , Proteína con Dominio Pirina 3 de la Familia NLR , Purinas , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Interleucina-1beta/metabolismo , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacos , Animales , Humanos , Ratones , Purinas/farmacología , Purinas/química , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/metabolismo , Adyuvantes Inmunológicos/farmacología , Adyuvantes Inmunológicos/química , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Linfocitos T/inmunología , Ratones Endogámicos C57BL , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Liposomas/química , Vacunas contra el Cáncer/farmacología , Vacunas contra el Cáncer/inmunología , Femenino , AminopiridinasRESUMEN
Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6 inhibitors) can significantly extend tumor response in patients with metastatic luminal A breast cancer, yet intrinsic and acquired resistance remains a prevalent issue. Understanding the molecular features of CDK4/6 inhibitor sensitivity and the potential efficacy of their combination with novel targeted cell death inducers may lead to improved patient outcomes. Herein, we demonstrate that ferroptosis, a form of regulated cell death driven by iron-dependent phospholipid peroxidation, partly underpins the efficacy of CDK4/6 inhibitors. Mechanistically, CDK4/6 inhibitors downregulate the cystine transporter SLC7A11 by inhibiting SP1 binding to the SLC7A11 promoter region. Furthermore, SLC7A11 is identified as critical for the intrinsic sensitivity of luminal A breast cancer to CDK4/6 inhibitors. Both genetic and pharmacological inhibition of SP1 or SLC7A11 enhances cell sensitivity to CDK4/6 inhibitors and synergistically inhibits luminal A breast cancer growth when combined with CDK4/6 inhibitors in vitro and in vivo. Our data highlight the potential of targeting SLC7A11 in combination with CDK4/6 inhibitors, supporting further investigation of combination therapy in luminal A breast cancer.