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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
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
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.
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Disponibilidad Biológica , Quinasa 6 Dependiente de la Ciclina , Flavanonas , Inhibidores de Proteínas Quinasas , Animales , Humanos , Ratas , Administración Oral , Aminopiridinas/farmacocinética , Aminopiridinas/farmacología , Aminopiridinas/administración & dosificación , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Biopotenciadores/farmacología , Células CACO-2 , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Citocromo P-450 CYP3A/metabolismo , Inhibidores Enzimáticos del Citocromo P-450/farmacología , Inhibidores Enzimáticos del Citocromo P-450/administración & dosificación , Flavanonas/administración & dosificación , Flavanonas/farmacología , Simulación del Acoplamiento Molecular , Permeabilidad , Piperazinas/farmacocinética , Piperazinas/farmacología , Piperazinas/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacocinética , Purinas/farmacocinética , Purinas/administración & dosificación , Purinas/farmacología , Piridinas/farmacocinética , Piridinas/farmacología , Piridinas/administración & dosificación , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Does incorporating Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors into endocrine therapy (ET) effectively enhance survival outcomes, notably overall survival (OS), among individuals with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer? This remains a clinical controversy. We compared the antitumor efficacy and adverse effects (AEs) between CDK4/6 inhibitors + ET (CET) and placebo + ET (PET) by conducting a phase III randomized controlled trials (RCTs) based meta-analysis. METHODS: Seven databases were searched to identify eligible studies, comprising Phase III RCTs comparing CET to PET. The primary endpoints were OS and progression-free survival (PFS), with secondary endpoints including responses and adverse events (AEs). RESULTS: Seven RCTs (DAWNA-2, MONALEESA-2, MONALEESA-3, MONALEESA-7, MONARCH-3, PALOMA-2, and PALOMA-4) were included. The CET group exhibited significantly improved OS (HR: 0.81 [0.74, 0.88]), PFS (HR: 0.57 [0.52, 0.63]), objective response rate (RR: 1.31 [1.20, 1.43]), and clinical benefit rate (RR: 1.11 [1.07, 1.15]). These benefits were consistent across almost all subgroups. Additionally, the CET group showed better overall survival rates (OSR) from 24 to 60 months (OSR 24-60 m) and progression-free survival rates (PFSR) from 6 to 60 months (PFSR 6-60 m). However, more total AEs, grade 3-5 AEs, and serious AEs were found in CET group. The top 5 grade 3-5 AEs in the CET group were neutropenia (59.39%), leukopenia (24.11%), decreased white blood cell count (12.99%), hypertension (7.03%), and increased alanine aminotransferase (5.91%). CONCLUSIONS: The superiority of CET over PET in HR+/HER2- advanced breast cancer is evident, showing improved survival and responses. Nonetheless, the higher incidence of AEs, specifically hematologic AEs, requires cautious attention.
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Antineoplásicos Hormonales , 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 , Femenino , Humanos , Antineoplásicos Hormonales/efectos adversos , Antineoplásicos Hormonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/metabolismo , Ensayos Clínicos Fase III como Asunto , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismoAsunto(s)
Neoplasias de la Mama , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Inhibidores de Proteínas Quinasas , Humanos , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Inhibidores de Proteínas Quinasas/uso terapéutico , Antineoplásicos/uso terapéutico , Terapia Molecular DirigidaRESUMEN
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.
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Aminopiridinas , Neoplasias de la Mama , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Piperazinas , Inhibidores de Proteínas Quinasas , Purinas , Piridinas , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Femenino , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Persona de Mediana Edad , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Piridinas/uso terapéutico , Estudios Retrospectivos , Anciano , Piperazinas/uso terapéutico , Aminopiridinas/uso terapéutico , Purinas/uso terapéutico , Taiwán , Inhibidores de Proteínas Quinasas/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Resultado del Tratamiento , Metástasis de la Neoplasia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Pueblo AsiaticoRESUMEN
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
BACKGROUND AND OBJECTIVES: Numerous clinical concerns have been expressed regarding the potential worsening of cyclin-dependent kinase 4/6 inhibitor effects in breast cancer patients because of co-administration of proton pump inhibitors. Hence, this study evaluated the effects of proton pump inhibitors on the pharmacokinetics of palbociclib and ribociclib in terms of cytochrome P450 (CYP) 3A4 and P-glycoprotein involvement. METHODS: The effects of omeprazole and rabeprazole on drug metabolism and efflux of these drugs were investigated using molecular docking, metabolic stability assay in rat liver microsomes, human recombinant CYP3A4 (rCYP3A4) enzymes, and Caco-2 cell monolayers, and in vivo pharmacokinetics with omeprazole and rabeprazole in (5 and 10 mg/kg) 30 min and 7 days before orally dosing palbociclib and ribociclib (10 mg/kg). RESULTS: Omeprazole and rabeprazole inhibited CYP3A4 enzyme activity in rCYP3A4 baculosomes with a 50-60% inhibition at 30 µM. Additionally, both omeprazole and rabeprazole (10 µm) significantly reduced the P-glycoprotein-mediated drug efflux of palbociclib and ribociclib. The 7-day pretreatment of omeprazole at a dose of 10 mg/kg resulted in 24% and 26% reductions in palbociclib's mean maximum plasma concentration) Cmax and area under the plasma concentration-time curve (AUC0-24 h), respectively. Palbociclib's pharmacokinetics were not significantly altered by the pretreatment with rabeprazole; however, ribociclib pharmacokinetics exhibited an 83.94% increase in AUC0-24 h. CONCLUSION: The findings indicate that long-term treatment with therapeutic doses of both omeprazole and rabeprazole can alter the pharmacokinetics of palbociclib and ribociclib. The co-administration of rabeprazole may alter the pharmacokinetics of palbociclib and ribociclib via CYP enzyme and P-glycoprotein inhibition.
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Aminopiridinas , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Citocromo P-450 CYP3A , Interacciones Farmacológicas , Microsomas Hepáticos , Omeprazol , Piperazinas , Inhibidores de la Bomba de Protones , Purinas , Piridinas , Rabeprazol , Animales , Inhibidores de la Bomba de Protones/farmacología , Inhibidores de la Bomba de Protones/administración & dosificación , Inhibidores de la Bomba de Protones/farmacocinética , Piperazinas/farmacocinética , Piperazinas/farmacología , Piperazinas/administración & dosificación , Humanos , Purinas/farmacocinética , Purinas/farmacología , Ratas , Piridinas/farmacocinética , Piridinas/farmacología , Piridinas/administración & dosificación , Rabeprazol/farmacología , Rabeprazol/administración & dosificación , Rabeprazol/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Omeprazol/farmacología , Omeprazol/farmacocinética , Omeprazol/administración & dosificación , Masculino , Células CACO-2 , Aminopiridinas/farmacocinética , Aminopiridinas/farmacología , Aminopiridinas/administración & dosificación , Microsomas Hepáticos/metabolismo , Microsomas Hepáticos/efectos de los fármacos , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Ratas Sprague-Dawley , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/administración & dosificación , Hígado/metabolismo , Hígado/efectos de los fármacos , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismoRESUMEN
The combination of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) with endocrine therapy (ET) is the standard-of-care for estrogen receptor (ER)-positive, HER2-negative (ER+/HER2- advanced/metastatic breast cancer (mBC). However, the impact of CDK4/6i on circulating immune cells and circulating tumor cells (CTCs) in patients receiving CDK4/6i and ET (CDK4/6i+ET) remains poorly understood. This was a prospective cohort study including 44 patients with ER+/HER2- mBC treated with CDK4/6i+ET in either first or second line. Peripheral blood samples were collected before (baseline) and 3 months (t2) after therapy. Immune cell's subsets were quantified by flow cytometry, and microfluidic-captured CTCs were counted and classified according to the expression of cytokeratin and/or vimentin. Patients were categorized according to response as responders (progression-free survival [PFS] ≥ 6.0 months; 79.1%) and non-responders (PFS < 6.0 months; 20.9%). CDK4/6i+ET resulted in significant changes in the hematological parameters, including decreased hemoglobin levels and increased mean corpuscular volume, as well as reductions in neutrophil, eosinophil, and basophil counts. Specific immune cell subsets, such as early-stage myeloid-derived suppressor cells, central memory CD4+ T cells, and Vδ2+ T cells expressing NKG2D, decreased 3 months after CDK4/6i+ET. Additionally, correlations between the presence of CTCs and immune cell populations were observed, highlighting the interplay between immune dysfunction and tumor dissemination. This study provides insights into the immunomodulatory effects of CDK4/6i+ET, underscoring the importance of considering immune dynamics in the management of ER+/HER2- mBC.
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Neoplasias de la Mama , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Células Neoplásicas Circulantes , Inhibidores de Proteínas Quinasas , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/sangre , Femenino , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/metabolismo , Células Neoplásicas Circulantes/patología , Células Neoplásicas Circulantes/efectos de los fármacos , Células Neoplásicas Circulantes/metabolismo , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Anciano , Metástasis de la Neoplasia , Adulto , Estudios ProspectivosRESUMEN
BACKGROUND: Copy number alterations (CNA) are acquired during the evolution of cancers from their early stage to metastatic stage. This study aims at analysing the clinical value of the identified metastasis-associated CNAs both in metastatic breast cancers (mBCs) and early breast cancers (eBCs). METHODS: Single-nucleotide polymorphism (SNP)-array was performed on 926 biopsies from mBC patients, enrolled in SAFIR02-BREAST prospective trial. CNA profiles of eBCs from The Cancer Genome Atlas Breast Invasive Carcinoma (n = 770), Molecular Taxonomy of Breast Cancer International Consortium (n = 1620) and PACS04 trial (n = 243) cohorts were used as references for comparing mBCs and eBCs CNA profiles. Overall survival was the considered survival endpoint. RESULTS: Among the twenty-one genes frequently altered in ER + /HER2- mBCs: focal amplification of TERT was associated with poor outcome in the ER + /HER2- mBC population. Among the ER + /HER2- mBCs patients for whom CDK4/6 inhibitors information before biopsies collection was available: we identified seven genes on post-treatment biopsies, including the cyclin-dependent kinase 4 (CDK4), which was amplified in 9.8% of the ER + /HER2- mBCs pretreated population, as compared to 1.5% in the ER + /HER2- mBCs unpretreated population (P = 2.82E-04) as well as the 3 eBC populations. CDK4 amplification was associated with poor outcome in the ER + /HER2- eBCs. CONCLUSIONS: This study provides insights into the biology of mBCs and identifies clinically useful genomic features for future improvement of breast cancer patient management.
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Biomarcadores de Tumor , Neoplasias de la Mama , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Variaciones en el Número de Copia de ADN , Resistencia a Antineoplásicos , Humanos , Neoplasias de la Mama/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Femenino , Quinasa 4 Dependiente de la Ciclina/genética , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/genética , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Biomarcadores de Tumor/genética , Pronóstico , Resistencia a Antineoplásicos/genética , Metástasis de la Neoplasia , Inhibidores de Proteínas Quinasas/uso terapéutico , Polimorfismo de Nucleótido Simple , Persona de Mediana Edad , Receptor ErbB-2/genética , Estudios Prospectivos , Adulto , Telomerasa/genética , AncianoRESUMEN
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.
Asunto(s)
Aminopiridinas , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Piperazinas , Inhibidores de Proteínas Quinasas , Purinas , Piridinas , Femenino , Humanos , Sistemas de Registro de Reacción Adversa a Medicamentos/estadística & datos numéricos , Aminopiridinas/efectos adversos , Antineoplásicos/efectos adversos , Bencimidazoles/efectos adversos , Estudios de Casos y Controles , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Farmacovigilancia , Piperazinas/efectos adversos , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Purinas/efectos adversos , Piridinas/efectos adversos , Estados Unidos/epidemiología , United States Food and Drug AdministrationAsunto(s)
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 , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Femenino , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Receptor ErbB-2/metabolismo , Receptor ErbB-2/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , AncianoRESUMEN
Ribociclib (RIB), a tyrosine kinase inhibitor, exhibits promising antitumor efficacy and controlled toxicity in HR+/HER2- breast cancer patients, which is closely related to the binding with plasma proteins. This study utilized a combination of spectroscopic techniques including UV spectroscopy, fluorescence spectroscopy, and circular dichroism (CD) as well as molecular docking and molecular dynamic simulation to clarify the binding mechanism between bovine serum albumin (BSA) and RIB. The findings demonstrated that RIB produced a 1:1 stoichiometric complex with BSA, which quenched BSA's fluorescence in the manner of the static quenching mechanism. Site labelling experiments pinpointed Site III on BSA as the primary binding site for RIB, a finding validated by molecular docking. Van der Waals forces and hydrogen bonding interactions as key drivers in the formation of RIB-BSA complexes, a conclusion supported by molecular docking. Molecular simulation studies suggested that the insertion of RIB into the hydrophobic cavity (Site III) of BSA induced subtle conformational changes in the BSA protein, and CD measurements confirmed alterations in BSA secondary structure content. Synchronous and three-dimensional fluorescence spectroscopy further demonstrated that RIB decreased the hydrophobicity of the microenvironment surrounding tyrosine and tryptophan residues. These findings offer valuable insights into the pharmacokinetics and structural modifications of RIB.
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Aminopiridinas , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Unión Proteica , Purinas , Albúmina Sérica Bovina , Albúmina Sérica Bovina/química , Albúmina Sérica Bovina/metabolismo , Aminopiridinas/química , Aminopiridinas/metabolismo , Purinas/química , Purinas/metabolismo , Animales , Bovinos , Sitios de Unión , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 4 Dependiente de la Ciclina/química , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/química , Espectrometría de Fluorescencia , Dicroismo Circular , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/metabolismoRESUMEN
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.
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Antineoplásicos , Ciclina D1 , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Transición Epitelial-Mesenquimal , Factor de Transcripción STAT3 , Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/metabolismo , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Transición Epitelial-Mesenquimal/efectos de los fármacos , Línea Celular Tumoral , Ciclina D1/metabolismo , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Proteínas Proto-Oncogénicas c-myc/metabolismo , Femenino , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Ligandos , Carcinogénesis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Platino (Metal)/química , Platino (Metal)/farmacología , Compuestos Organoplatinos/farmacología , Compuestos Organoplatinos/química , Compuestos Organoplatinos/síntesis químicaRESUMEN
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.
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Antineoplásicos , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Desarrollo de Medicamentos , Resistencia a Antineoplásicos , Neoplasias , Patentes como Asunto , Inhibidores de Proteínas Quinasas , Humanos , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Antineoplásicos/farmacología , AnimalesRESUMEN
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.
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Neoplasias de la Mama , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Resistencia a Antineoplásicos , Factor de Transcripción Asociado a Microftalmía , N-Acetilglucosaminiltransferasas , Piperazinas , Piridinas , Humanos , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Quinasa 6 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Factor de Transcripción Asociado a Microftalmía/metabolismo , Factor de Transcripción Asociado a Microftalmía/genética , Femenino , Resistencia a Antineoplásicos/efectos de los fármacos , Piperazinas/farmacología , Piridinas/farmacología , Línea Celular Tumoral , N-Acetilglucosaminiltransferasas/metabolismo , N-Acetilglucosaminiltransferasas/antagonistas & inhibidores , N-Acetilglucosaminiltransferasas/genética , Animales , Ratones , Inhibidores de Proteínas Quinasas/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
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.
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Neoplasias de la Mama , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Receptor ErbB-2 , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/mortalidad , Receptor ErbB-2/metabolismo , Receptor ErbB-2/antagonistas & inhibidores , Estudios Retrospectivos , Persona de Mediana Edad , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Anciano , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Adulto , Supervivencia sin Progresión , Receptores de Estrógenos/metabolismoRESUMEN
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.
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Sistemas de Registro de Reacción Adversa a Medicamentos , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Trastornos Mentales , Farmacovigilancia , Inhibidores de Proteínas Quinasas , United States Food and Drug Administration , Humanos , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Femenino , Masculino , Sistemas de Registro de Reacción Adversa a Medicamentos/estadística & datos numéricos , Estados Unidos/epidemiología , Persona de Mediana Edad , Anciano , Trastornos Mentales/inducido químicamente , Trastornos Mentales/epidemiología , Adulto , United States Food and Drug Administration/tendencias , Inhibidores de Proteínas Quinasas/efectos adversos , Adulto Joven , Adolescente , Anciano de 80 o más AñosRESUMEN
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.
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Aminopiridinas , Creatinina , Quinasa 4 Dependiente de la Ciclina , Piperazinas , Purinas , Piridinas , Humanos , Purinas/efectos adversos , Purinas/administración & dosificación , Purinas/uso terapéutico , Creatinina/sangre , Piperazinas/efectos adversos , Piperazinas/administración & dosificación , Piperazinas/uso terapéutico , Aminopiridinas/efectos adversos , Aminopiridinas/administración & dosificación , Aminopiridinas/uso terapéutico , Femenino , Piridinas/efectos adversos , Piridinas/administración & dosificación , Persona de Mediana Edad , Anciano , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Neoplasias de la Mama/tratamiento farmacológico , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Adulto , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , MasculinoRESUMEN
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.