Background:Regulatory proteins involved in human cellular division and proliferation,cyclin-dependent kinases 4 and 6(CDK4/6)are overexpressed in numerous cancers,including triple-negative breast cancer(TNBC).TNBC is ...Background:Regulatory proteins involved in human cellular division and proliferation,cyclin-dependent kinases 4 and 6(CDK4/6)are overexpressed in numerous cancers,including triple-negative breast cancer(TNBC).TNBC is a common pathological subtype of breast cancer that is prone to recurrence and metastasis,and has a single treatment method.As one of the CDK4/6 inhibitors,abemaciclib can effectively inhibit the growth of breast tumors.In this study,we synthesized LA-D-B1,a derivative of Abemaciclib,and investigated its anti-tumor effects in breast cancer.Methods:Cellular viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)assay.Cell cloning and migration abilities were determined by colony formation assay and wound healing assay.Cell invasion abilities and adhesion were determined by cell invasion assay and cell adhesion assay.The impact of compound LA-D-B1 on cell proliferation and the cell cycle was analyzed through Western blotting,which quantified the levels of proteins associated with the cyclin-dependent kinase(CDK)4/6-cyclin D-Rb-E2F pathway.The in vivo anti-tumor activity of compound LA-D-B1 was investigated using a chick chorioallantoic membrane(CAM)model.Results:The study demonstrated that LA-D-B1 effectively suppressed breast cancer cell proliferation,induced apoptosis,and caused cell cycle arrest.Furthermore,LA-D-B1 reduced the expression of key proteins in the CDK4/6-cyclin D-Rb-E2F pathway,including CDK4,CDK6 and E2F1.The results also indicated significant antitumor activity of LA-D-B1 in a transplanted tumor model.Conclusion:In this study,LA-D-B1 demonstrated a potent anti-tumor effect by effectively suppressing cell proliferation and inhibiting cell cycle progression in breast cancer.These findings highlight the potential of LA-D-B1 as a valuable compound for enhancing therapeutic outcomes and controlling the progression of breast cancer.展开更多
Endocrine therapy(ET)is the therapy backbone of hormone receptor(HR)-positive and human epidermal growth factor receptor 2(HER2)-negati ve advanced breast cancer.However,there are about 20%HR positive patients with no...Endocrine therapy(ET)is the therapy backbone of hormone receptor(HR)-positive and human epidermal growth factor receptor 2(HER2)-negati ve advanced breast cancer.However,there are about 20%HR positive patients with no response to ET due to primary or acquired ET resistance.In this background,many agents have been studied to overcome ET resistance and of which the important agents are cyclin-dependent kinase 4/6(CDK4/6)inhibitors.The prognosis of advanced breast cancer has been improved by combing ET with CDK4/6 inhibitors.In this review,we mainly focused on the CDK4/6 inhibitors in the treatment of HR-positive,HER2-negative advanced breast cancer and discussed the action mechanisms of CDK4/6 inhibitors alone or combined with ET.We also summarized several molecular features that would predict response or resistance to CDK4/6 inhibitors.In addition,we put forward possible strategies to overcome CDK4/6 inhibitor resistance according to the latest research.展开更多
Introduction: Proton pump inhibitors (PPi) are widely prescribed, including in patients undergoing treatment for advanced breast cancer (ABC). Due to the pharmacokinetic characteristics of the CDK4/6 inhibitor (Ci) pa...Introduction: Proton pump inhibitors (PPi) are widely prescribed, including in patients undergoing treatment for advanced breast cancer (ABC). Due to the pharmacokinetic characteristics of the CDK4/6 inhibitor (Ci) palbociclib a drug interaction with PPi was hypothesized. It was shown in a retrospective study that this association was an independent predictive factor for worse progression-free survival (PFS). Objective: To verify the impact of concomitant administration of PPi with Ci on overall survival (OS) and PFS. Material and Methods: This is a retrospective cohort study of patients treated with Ci for HR+HER2-ABC in the period from Feb/2017 to Aug/2020. SPSS software was used for data processing. Univariate analysis was done by the Kaplan-Meier method and log-rank test, and multivariate analysis by COX regression. P-value < 0.05 was considered significant. Results: 80 patients were included. The median age at diagnosis of ABC was 56 years (25 - 75). Treatment with Ci was 1st line for ABC in 68.8%. Choice of Ci was palbociclib in 73.8% (n = 59) and ribociclib in 26.3% (n = 21). The hormone partner was a nonsteroidal aromatase inhibitor in 45.0%, and fulvestrant in 55.0% of cases. 37.5% of patients were on PPi, and 70.0% of them were during the entire treatment (23.3% omeprazole, 73.4% pantoprazole, 3.3% others). Patients taking concomitant PPi and Ci had lower OS (OS-3 years 42.6% vs. 63.4%, p = 0.254) and PFS (PFS med 15 m. vs. 21 m., p = 0.733), although with no statistically significant difference. Discussion: In the sample, there was a numerical difference, without the statistical significance in the use of PPi in the survival of patients under Ci. This difference could be more evident with a longer follow-up and a larger sample size. This study intends to alert to the growing importance of checking for drug interactions. Polymedication, advanced age and the presence of several comorbidities are real problems in patients with ABC. Conclusion: Real-world data from this center demonstrate a negative, non-statistically significant impact of PPi treatment on survival outcomes, in patients treated with Ci for HR+HER2-ABC.展开更多
Objective To review the domestic and foreign economic studies on CDK4/6 inhibitors in first-line or second-line treatment of HR+/HER2-advanced breast cancer,and to analyze the main methodologies and research results.M...Objective To review the domestic and foreign economic studies on CDK4/6 inhibitors in first-line or second-line treatment of HR+/HER2-advanced breast cancer,and to analyze the main methodologies and research results.Methods Systematic literature review was used to search PubMed,EMBASE,Cochrane Library,CNKI,CBM,and Wanfang database.The incremental cost-effectiveness ratio was taken as the main outcome index,and all pharmacoeconomic evaluations with CDK4/6 inhibitors as intervention measures were included,such as Palbociclib,Ribociclib,and Abemaciclib.According to the Quality of Health Economic Studies Instrument,the quality of the included articles was evaluated,and then the included literature was analyzed.Results and Conclusion A total of 16 pharmacoeconomic evaluation studies were included,mainly from the perspective of national healthcare systems or third-party payers.Only 2 studies focused on second-line treatment,and the remaining treatment levels were first-line treatment.In terms of model structure,7 studies adopted the Markov model,6 studies adopted the PSM model,and 3 studies adopted the DES model.The basic analysis results showed that CDK4/6 inhibitor combined with endocrine regimen was not economical compared with endocrine alone regimen when the threshold was the conventional willingness to pay(WTP)value of each country.The uncertainty analysis included deterministic sensitivity analysis and probability sensitivity analysis.The included studies are all Cost-Utility Analysis with high-quality evaluation,which can provide evidence support for health-related decision-makers in decision-making.It can also provide methodological reference for the economic evaluation of other targeted drugs.展开更多
This comprehensive review delves into the current updates and challenges associated with the management of low-grade gliomas(LGG),the predominant primary tumors in the central nervous system.With a general incidence r...This comprehensive review delves into the current updates and challenges associated with the management of low-grade gliomas(LGG),the predominant primary tumors in the central nervous system.With a general incidence rate of 5.81 per 100000,gliomas pose a significant global concern,necessitating advancements in treatment techniques to reduce mortality and morbidity.This review places a particular focus on immunotherapies,discussing promising agents such as Zotiraciclib and Lerapolturev.Zotiraciclib,a CDK9 inhibitor,has demonstrated efficacy in glioblastoma treatment in preclinical and clinical studies,showing its potential as a therapeutic breakthrough.Lerapolturev,a viral immunotherapy,induces inflammation in glioblastoma and displays positive outcomes in both adult and pediatric patients.Exploration of immunotherapy extends to Pembrolizumab,Nivolumab,and Entrectinib,revealing the challenges and variabilities in patient responses.Despite promising preclinical data,the monoclonal antibody Depatuxizumab has proven ineffective in glioblastoma treatment,emphasizing the critical need to understand resistance mechanisms.The review also covers the success of radiation therapy in pediatric LGG,with evolving techniques,such as proton therapy,showing potential improvements in patient quality of life.Surgical treatment is discussed in the context of achieving a balance between preserving the patient’s quality of life and attaining gross total resection,with the extent of surgical resection significantly influencing the survival outcomes.In addition to advancements in cancer vaccine development,this review highlights the evolving landscape of LGG treatment,emphasizing a shift toward personalized and targeted therapies.Ongoing research is essential for refining strategies and enhancing outcomes in the management of LGG.展开更多
Skeletal muscle metastasis from breast cancer is a very rare presentation. We reported a case with breast cancer metastatic to skeletal muscle, bone, peritoneum and lymph node at presentation detected in FDG PET-CT. A...Skeletal muscle metastasis from breast cancer is a very rare presentation. We reported a case with breast cancer metastatic to skeletal muscle, bone, peritoneum and lymph node at presentation detected in FDG PET-CT. A Core needle biopsy was performed from the left breast tail lesion. Immunohistochemistry showed hormonal positivity, Her2 negativity with low KI67. Patient was treated with combined CDK4 inhibitor and non-steroidal aromatase inhibitors with regressive course in the PET-CT after the 1st 3 months. More studies should investigate the prognosis and proper management of skeletal muscle metastasis in breast cancer.展开更多
CDK4/6 inhibitors are the standard treatment in advanced HR+/HER2-breast cancer patients.Nevertheless,the resistance to CDK4/6 inhibitors is inevitable and the strategies to overcome resistance are of great interest.H...CDK4/6 inhibitors are the standard treatment in advanced HR+/HER2-breast cancer patients.Nevertheless,the resistance to CDK4/6 inhibitors is inevitable and the strategies to overcome resistance are of great interest.Here,we show that the palbociclibresistant breast cancer cells expressed significantly higher levels of Cyclin D1 and CDK4 proteins because of upregulated protein synthesis.Silencing Cyclin D1 or CDK4 led to cell cycle arrest while silencing Cyclin E1 or CDK2 restored the sensitivity to palbociclib.Furthermore,PI3K/mTOR pathway was hyper-activated in palbociclib-resistant cells,leading to more phosphorylated 4E-BP1 and higher levels of Cyclin D1 and CDK4 translation.Targeting PI3K/mTOR pathway with a specific PI3Kαinhibitor(BYL719)or an mTOR inhibitor(everolimus)reduced the protein levels of Cyclin D1 and CDK4,and restored the sensitivity to palbociclib.The tumor samples expressed significantly higher levels of Cyclin D1,CDK4,p-AKT and p-4E-BP1 after progression on palbociclib treatment.In conclusion,our findings suggest that overexpressed Cyclin D1 and CDK4 proteins lead to the resistance to CDK4/6 inhibitor and PI3K/mTOR inhibitors are able to restore the sensitivity to CDK4/6 inhibitors,which provides the biomarker and rationale for the combinational use of CDK4/6 inhibitors and PI3K/mTOR inhibitors after CDK4/6 inhibitor resistance in breast cancer.展开更多
CDK4/6 inhibitors are routinely recommended agents for the treatment of advanced HR+HER2-breast cancer.However,their therapeutic effectiveness in triple-negative breast cancer(TNBC)remains controversial.Here,we observ...CDK4/6 inhibitors are routinely recommended agents for the treatment of advanced HR+HER2-breast cancer.However,their therapeutic effectiveness in triple-negative breast cancer(TNBC)remains controversial.Here,we observed that the expression level of fibrous sheath interacting protein 1(FSIP1)could predict the treatment response of TNBC to CDK4/6 inhibitors.High FSIP1 expression level was related to a poor prognosis in TNBC,which was associated with the ability of FSIP1 to promote tumor cell proliferation.FSIP1 downregulation led to slowed tumor growth and reduced lung metastasis in TNBC.FSIP1knockout caused cell cycle arrest at the G0/G1 phase and reduced treatment sensitivity to CDK4/6 inhibitors by inactivating the Nanog/CCND1/CDK4/6 pathway.FSIP1 could form a complex with Nanog,protecting it from ubiquitination and degradation,which may facilitate the rapid cell cycle transition from G0/G1 to S phase and exhibit enhanced sensitivity to CDK4/6 inhibitors.Our findings suggest that TNBC patients with high FSIP1 expression levels may be suitable candidates for CDK4/6 inhibitor treatment.展开更多
Abnormally activated CDK9 participates in the super-enhancer mediated transcription of short-lived proteins required for cancer cell survival.Targeting CDK9 has shown potent anti-tumor activity in clinical trials amon...Abnormally activated CDK9 participates in the super-enhancer mediated transcription of short-lived proteins required for cancer cell survival.Targeting CDK9 has shown potent anti-tumor activity in clinical trials among different cancers.However,the study and knowledge on drug resistance to CDK9 inhibitors are very limited.In this study,we established an AML cell line with acquired resistance to a highly selective CDK9 inhibitor BAY1251152.Through genomic sequencing,we identified in the kinase domain of CDK9 a mutation L156F,which is also a coding SNP in the CDK9 gene.By knocking in L156F into cancer cells using CRISPR/Cas9,we found that single CDK9 L156F could drive the resistance to CDK9 inhibitors,not only ATP competitive inhibitor but also PROTAC degrader.Mechanistically,CDK9 L156F disrupts the binding with inhibitors due to steric hindrance,further,the mutation affects the thermal stability and catalytic activity of CDK9 protein.To overcome the drug resistance mediated by the CDK9-L156F mutation,we discovered a compound,IHMT-CDK9-36 which showed potent inhibition activity both for CDK9 WT and L156F mutant.Together,we report a novel resistance mechanism for CDK9 inhibitors and provide a novel chemical scaffold for the future development of CDK9 inhibitors.展开更多
Cellular growth,development,and differentiation are tightly controlled by a conserved biological mechanism:the cell cycle.This cycle is primarily regulated by cyclin-dependent kinase(CDK)-cyclin complexes,checkpoint k...Cellular growth,development,and differentiation are tightly controlled by a conserved biological mechanism:the cell cycle.This cycle is primarily regulated by cyclin-dependent kinase(CDK)-cyclin complexes,checkpoint kinases,and CDK inhibitors.Deregulation of the cell cycle is a hallmark of the transformation of normal cells into tumor cells.Given its importance in tumorigenesis,several cell cycle inhibitors have emerged as potential therapeutic drugs for the treatment of cancers-both as singleagent therapy and in combination with traditional cytotoxic or molecular targeting agents.In this review,we discuss the mechanisms underlying cell cycle regulation and present small-molecule anticancer drugs that are under development,including both pan-CDK inhibitors and CDK4/6-selective inhibitors.In addition,we provide an outline of some promising CDK inhibitors currently in preclinical and clinical trials that target cell cycle abnormalities in various cancers.展开更多
Cyclin-dependent kinases 4 and 6 inhibitors(CDK4/6i)have been demonstrated to trigger antitumor immunity for tumor regression.However,the therapeutic performance of CDK4/6i-meadiated cancer immunotherapy was impaired ...Cyclin-dependent kinases 4 and 6 inhibitors(CDK4/6i)have been demonstrated to trigger antitumor immunity for tumor regression.However,the therapeutic performance of CDK4/6i-meadiated cancer immunotherapy was impaired by the immunosuppressive tumor microenvironment(ITM)due to overexpression of programmed death ligand 1(PD-L1)on the surface of cancer cell membrane.To improve the immunotherapeutic performance of CDK4/6i,we herein developed endosomal acidactivatable micelleplex for si RNA delivery and PD-L1 knockdown in the tumor cells in vitro and in vivo.We further demonstrated that the combination of PD-L1 knockdown and CDK4/6 inhibition facilitated intratumoral infiltration of cytotoxic T lymphocytes(CTLs),and elicited protective immune response and efficiently suppressed tumor growth in vivo.This study revealed the importance of molecular design of the micelleplex for highly efficient si RNA delivery,which might provide a novel insight for RNAi-based cancer immunotherapy.展开更多
Cyclin-dependent kinase 4 and 6(CDK4/6)inhibitors combined with endocrine therapy have transformed the treatment of estrogen receptor-positive(ER+)and human epidermal growth factor receptor 2 negative(HER2-)metastatic...Cyclin-dependent kinase 4 and 6(CDK4/6)inhibitors combined with endocrine therapy have transformed the treatment of estrogen receptor-positive(ER+)and human epidermal growth factor receptor 2 negative(HER2-)metastatic breast cancer.However,some patients do not respond to this treatment,and patients inevitably develop resistance,such that novel biomarkers are needed to predict primary resistance,monitor treatment response for acquired resistance,and personalize treatment strategies.Circumventing the spatial and temporal limitations of tissue biopsy,newly developed liquid biopsy approaches have the potential to uncover biomarkers that can predict CDK4/6 inhibitor efficacy and resistance in breast cancer patients through a simple blood test.Studies on circulating tumor DNA(ctDNA)-based liquid biopsy biomarkers of CDK4/6 inhibitor resistance have focused primarily on genomic alterations and have failed thus far to identify clear and clinically validated predictive biomarkers,but emerging epigenetic ctDNA methodologies hold promise for further discovery.The present review outlines recent advances and future directions in ctDNA-based biomarkers of CDK4/6 inhibitor treatment response.展开更多
Approximately 20%of invasive breast cancers have upregulation/gene amplification of the oncogene human epidermal growth factor receptor-2(HER2/ErbB2).Of these,some also express steroid receptors(the so-called Luminal ...Approximately 20%of invasive breast cancers have upregulation/gene amplification of the oncogene human epidermal growth factor receptor-2(HER2/ErbB2).Of these,some also express steroid receptors(the so-called Luminal B subtype),whereas others do not(the HER2 subtype).HER2 abnormal breast cancers are associated with a worse prognosis,chemotherapy resistance,and sensitivity to selected anti-HER2 targeted therapeutics.Transcriptional data from over 3000 invasive breast cancers suggest that this approach is overly simplistic;rather,the upregulation of HER2 expression resulting from gene amplification is a driver event that causes major transcriptional changes involving numerous genes and pathways in breast cancer cells.Most notably,this includes a shift from estrogenic dependence to regulatory controls driven by other nuclear receptors,particularly the androgen receptor.We discuss members of the HER receptor tyrosine kinase family,heterodimer formation,and downstream signaling,with a focus on HER2 associated pathology in breast carcinogenesis.The development and application of anti-HER2 drugs,including selected clinical trials,are discussed.In light of the many excellent reviews in the clinical literature,our emphasis is on recently developed and successful strategies to overcome targeted therapy resistance.These include combining anti-HER2 agents with programmed cell death-1 ligand or cyclin-dependent kinase 4/6 inhibitors,targeting crosstalk between HER2 and other nuclear receptors,lipid/cholesterol synthesis to inhibit receptor tyrosine kinase activation,and metformin,a broadly inhibitory drug.We seek to facilitate a better understanding of new approaches to overcome anti-HER2 drug resistance and encourage exploration of two other therapeutic interventions that may be clinically useful for HER+invasive breast cancer patients.展开更多
基金supported by the National Natural Science Foundation of China(82273167,82104174,81602626,12271068,82172558 and 82373112)Jiangsu Province Basic Research Program Natural Science Foundation(Outstanding Youth Fund Project,BK20220063)+7 种基金the Key Program of Basic Science(Natural Science)of Jiangsu Province(22KJA350001)“Huaguo Mountain Talent Plan”of Lianyungang City(Innovative Talents Liu Bin)Qing Lan Project of Jiangsu Universities(Outstanding Young Backbone Teachers,Ji Jing)the Natural Science Foundation of Jiangsu Higher Education Institutions of China(No.20KJB350008)Priority Academic Program Development of Jiangsu Higher Education Institutions,College Students’Innovative Entrepreneurial Training Plan Program(Project Nos.SY202211641640011,SY202311641640002 and SZ202311641640002)Chen Xiao-Ping Foundation for the Development of Science and Technology of Hubei Province(Project No.CXPJJH123003-027)the Distinguished Young Scholars of Nanjing(JQX20008)Scientific Research Foundation for Returned Scholars of Tongji Hospital(Project 2022hgry021).
文摘Background:Regulatory proteins involved in human cellular division and proliferation,cyclin-dependent kinases 4 and 6(CDK4/6)are overexpressed in numerous cancers,including triple-negative breast cancer(TNBC).TNBC is a common pathological subtype of breast cancer that is prone to recurrence and metastasis,and has a single treatment method.As one of the CDK4/6 inhibitors,abemaciclib can effectively inhibit the growth of breast tumors.In this study,we synthesized LA-D-B1,a derivative of Abemaciclib,and investigated its anti-tumor effects in breast cancer.Methods:Cellular viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)assay.Cell cloning and migration abilities were determined by colony formation assay and wound healing assay.Cell invasion abilities and adhesion were determined by cell invasion assay and cell adhesion assay.The impact of compound LA-D-B1 on cell proliferation and the cell cycle was analyzed through Western blotting,which quantified the levels of proteins associated with the cyclin-dependent kinase(CDK)4/6-cyclin D-Rb-E2F pathway.The in vivo anti-tumor activity of compound LA-D-B1 was investigated using a chick chorioallantoic membrane(CAM)model.Results:The study demonstrated that LA-D-B1 effectively suppressed breast cancer cell proliferation,induced apoptosis,and caused cell cycle arrest.Furthermore,LA-D-B1 reduced the expression of key proteins in the CDK4/6-cyclin D-Rb-E2F pathway,including CDK4,CDK6 and E2F1.The results also indicated significant antitumor activity of LA-D-B1 in a transplanted tumor model.Conclusion:In this study,LA-D-B1 demonstrated a potent anti-tumor effect by effectively suppressing cell proliferation and inhibiting cell cycle progression in breast cancer.These findings highlight the potential of LA-D-B1 as a valuable compound for enhancing therapeutic outcomes and controlling the progression of breast cancer.
文摘Endocrine therapy(ET)is the therapy backbone of hormone receptor(HR)-positive and human epidermal growth factor receptor 2(HER2)-negati ve advanced breast cancer.However,there are about 20%HR positive patients with no response to ET due to primary or acquired ET resistance.In this background,many agents have been studied to overcome ET resistance and of which the important agents are cyclin-dependent kinase 4/6(CDK4/6)inhibitors.The prognosis of advanced breast cancer has been improved by combing ET with CDK4/6 inhibitors.In this review,we mainly focused on the CDK4/6 inhibitors in the treatment of HR-positive,HER2-negative advanced breast cancer and discussed the action mechanisms of CDK4/6 inhibitors alone or combined with ET.We also summarized several molecular features that would predict response or resistance to CDK4/6 inhibitors.In addition,we put forward possible strategies to overcome CDK4/6 inhibitor resistance according to the latest research.
文摘Introduction: Proton pump inhibitors (PPi) are widely prescribed, including in patients undergoing treatment for advanced breast cancer (ABC). Due to the pharmacokinetic characteristics of the CDK4/6 inhibitor (Ci) palbociclib a drug interaction with PPi was hypothesized. It was shown in a retrospective study that this association was an independent predictive factor for worse progression-free survival (PFS). Objective: To verify the impact of concomitant administration of PPi with Ci on overall survival (OS) and PFS. Material and Methods: This is a retrospective cohort study of patients treated with Ci for HR+HER2-ABC in the period from Feb/2017 to Aug/2020. SPSS software was used for data processing. Univariate analysis was done by the Kaplan-Meier method and log-rank test, and multivariate analysis by COX regression. P-value < 0.05 was considered significant. Results: 80 patients were included. The median age at diagnosis of ABC was 56 years (25 - 75). Treatment with Ci was 1st line for ABC in 68.8%. Choice of Ci was palbociclib in 73.8% (n = 59) and ribociclib in 26.3% (n = 21). The hormone partner was a nonsteroidal aromatase inhibitor in 45.0%, and fulvestrant in 55.0% of cases. 37.5% of patients were on PPi, and 70.0% of them were during the entire treatment (23.3% omeprazole, 73.4% pantoprazole, 3.3% others). Patients taking concomitant PPi and Ci had lower OS (OS-3 years 42.6% vs. 63.4%, p = 0.254) and PFS (PFS med 15 m. vs. 21 m., p = 0.733), although with no statistically significant difference. Discussion: In the sample, there was a numerical difference, without the statistical significance in the use of PPi in the survival of patients under Ci. This difference could be more evident with a longer follow-up and a larger sample size. This study intends to alert to the growing importance of checking for drug interactions. Polymedication, advanced age and the presence of several comorbidities are real problems in patients with ABC. Conclusion: Real-world data from this center demonstrate a negative, non-statistically significant impact of PPi treatment on survival outcomes, in patients treated with Ci for HR+HER2-ABC.
基金The cooperative project of Shenyang Pharmaceutical University and Zhonglian Medicine-“Research on the Marketing Strategy of Imported Drugs in China”(2020-0-4-048).
文摘Objective To review the domestic and foreign economic studies on CDK4/6 inhibitors in first-line or second-line treatment of HR+/HER2-advanced breast cancer,and to analyze the main methodologies and research results.Methods Systematic literature review was used to search PubMed,EMBASE,Cochrane Library,CNKI,CBM,and Wanfang database.The incremental cost-effectiveness ratio was taken as the main outcome index,and all pharmacoeconomic evaluations with CDK4/6 inhibitors as intervention measures were included,such as Palbociclib,Ribociclib,and Abemaciclib.According to the Quality of Health Economic Studies Instrument,the quality of the included articles was evaluated,and then the included literature was analyzed.Results and Conclusion A total of 16 pharmacoeconomic evaluation studies were included,mainly from the perspective of national healthcare systems or third-party payers.Only 2 studies focused on second-line treatment,and the remaining treatment levels were first-line treatment.In terms of model structure,7 studies adopted the Markov model,6 studies adopted the PSM model,and 3 studies adopted the DES model.The basic analysis results showed that CDK4/6 inhibitor combined with endocrine regimen was not economical compared with endocrine alone regimen when the threshold was the conventional willingness to pay(WTP)value of each country.The uncertainty analysis included deterministic sensitivity analysis and probability sensitivity analysis.The included studies are all Cost-Utility Analysis with high-quality evaluation,which can provide evidence support for health-related decision-makers in decision-making.It can also provide methodological reference for the economic evaluation of other targeted drugs.
文摘This comprehensive review delves into the current updates and challenges associated with the management of low-grade gliomas(LGG),the predominant primary tumors in the central nervous system.With a general incidence rate of 5.81 per 100000,gliomas pose a significant global concern,necessitating advancements in treatment techniques to reduce mortality and morbidity.This review places a particular focus on immunotherapies,discussing promising agents such as Zotiraciclib and Lerapolturev.Zotiraciclib,a CDK9 inhibitor,has demonstrated efficacy in glioblastoma treatment in preclinical and clinical studies,showing its potential as a therapeutic breakthrough.Lerapolturev,a viral immunotherapy,induces inflammation in glioblastoma and displays positive outcomes in both adult and pediatric patients.Exploration of immunotherapy extends to Pembrolizumab,Nivolumab,and Entrectinib,revealing the challenges and variabilities in patient responses.Despite promising preclinical data,the monoclonal antibody Depatuxizumab has proven ineffective in glioblastoma treatment,emphasizing the critical need to understand resistance mechanisms.The review also covers the success of radiation therapy in pediatric LGG,with evolving techniques,such as proton therapy,showing potential improvements in patient quality of life.Surgical treatment is discussed in the context of achieving a balance between preserving the patient’s quality of life and attaining gross total resection,with the extent of surgical resection significantly influencing the survival outcomes.In addition to advancements in cancer vaccine development,this review highlights the evolving landscape of LGG treatment,emphasizing a shift toward personalized and targeted therapies.Ongoing research is essential for refining strategies and enhancing outcomes in the management of LGG.
文摘Skeletal muscle metastasis from breast cancer is a very rare presentation. We reported a case with breast cancer metastatic to skeletal muscle, bone, peritoneum and lymph node at presentation detected in FDG PET-CT. A Core needle biopsy was performed from the left breast tail lesion. Immunohistochemistry showed hormonal positivity, Her2 negativity with low KI67. Patient was treated with combined CDK4 inhibitor and non-steroidal aromatase inhibitors with regressive course in the PET-CT after the 1st 3 months. More studies should investigate the prognosis and proper management of skeletal muscle metastasis in breast cancer.
基金supported by the Notional Natural Science Foundation of China(82061148016,81630074,81872141,81702630,81672622)Guangzhou Science and Technology Plan Key Projects(201804020076)+2 种基金Natural Science Foundation of Guangdong(2019A1515010146)Beijing Medical Award Foundation(YXJL-20200941-0760)China Postdoctoral Science Foundation(2021TQ0384,2021M703731)。
文摘CDK4/6 inhibitors are the standard treatment in advanced HR+/HER2-breast cancer patients.Nevertheless,the resistance to CDK4/6 inhibitors is inevitable and the strategies to overcome resistance are of great interest.Here,we show that the palbociclibresistant breast cancer cells expressed significantly higher levels of Cyclin D1 and CDK4 proteins because of upregulated protein synthesis.Silencing Cyclin D1 or CDK4 led to cell cycle arrest while silencing Cyclin E1 or CDK2 restored the sensitivity to palbociclib.Furthermore,PI3K/mTOR pathway was hyper-activated in palbociclib-resistant cells,leading to more phosphorylated 4E-BP1 and higher levels of Cyclin D1 and CDK4 translation.Targeting PI3K/mTOR pathway with a specific PI3Kαinhibitor(BYL719)or an mTOR inhibitor(everolimus)reduced the protein levels of Cyclin D1 and CDK4,and restored the sensitivity to palbociclib.The tumor samples expressed significantly higher levels of Cyclin D1,CDK4,p-AKT and p-4E-BP1 after progression on palbociclib treatment.In conclusion,our findings suggest that overexpressed Cyclin D1 and CDK4 proteins lead to the resistance to CDK4/6 inhibitor and PI3K/mTOR inhibitors are able to restore the sensitivity to CDK4/6 inhibitors,which provides the biomarker and rationale for the combinational use of CDK4/6 inhibitors and PI3K/mTOR inhibitors after CDK4/6 inhibitor resistance in breast cancer.
基金supported by the National Natural Science Foundation of China (82203804,81872159)345 Talent Project of Shengjing Hospital of China Medical University。
文摘CDK4/6 inhibitors are routinely recommended agents for the treatment of advanced HR+HER2-breast cancer.However,their therapeutic effectiveness in triple-negative breast cancer(TNBC)remains controversial.Here,we observed that the expression level of fibrous sheath interacting protein 1(FSIP1)could predict the treatment response of TNBC to CDK4/6 inhibitors.High FSIP1 expression level was related to a poor prognosis in TNBC,which was associated with the ability of FSIP1 to promote tumor cell proliferation.FSIP1 downregulation led to slowed tumor growth and reduced lung metastasis in TNBC.FSIP1knockout caused cell cycle arrest at the G0/G1 phase and reduced treatment sensitivity to CDK4/6 inhibitors by inactivating the Nanog/CCND1/CDK4/6 pathway.FSIP1 could form a complex with Nanog,protecting it from ubiquitination and degradation,which may facilitate the rapid cell cycle transition from G0/G1 to S phase and exhibit enhanced sensitivity to CDK4/6 inhibitors.Our findings suggest that TNBC patients with high FSIP1 expression levels may be suitable candidates for CDK4/6 inhibitor treatment.
基金supported by the National Natural Science Foundation of China(Grant Nos.81903650,32171479,82103976)the Natural Science Foundation of Anhui Province(Grant Nos.2008085MH274,2108085QH377,China)+2 种基金the Collaborative Innovation Program of Hefei Science Center,CAS(Grant No.2021HSC-CIP014,China)the CASHIPS Director’s Found(Grant Nos.YZJJZX202011,YZJJ2021QN38,China)supported by the High Magnetic Field Laboratory of Anhui Province。
文摘Abnormally activated CDK9 participates in the super-enhancer mediated transcription of short-lived proteins required for cancer cell survival.Targeting CDK9 has shown potent anti-tumor activity in clinical trials among different cancers.However,the study and knowledge on drug resistance to CDK9 inhibitors are very limited.In this study,we established an AML cell line with acquired resistance to a highly selective CDK9 inhibitor BAY1251152.Through genomic sequencing,we identified in the kinase domain of CDK9 a mutation L156F,which is also a coding SNP in the CDK9 gene.By knocking in L156F into cancer cells using CRISPR/Cas9,we found that single CDK9 L156F could drive the resistance to CDK9 inhibitors,not only ATP competitive inhibitor but also PROTAC degrader.Mechanistically,CDK9 L156F disrupts the binding with inhibitors due to steric hindrance,further,the mutation affects the thermal stability and catalytic activity of CDK9 protein.To overcome the drug resistance mediated by the CDK9-L156F mutation,we discovered a compound,IHMT-CDK9-36 which showed potent inhibition activity both for CDK9 WT and L156F mutant.Together,we report a novel resistance mechanism for CDK9 inhibitors and provide a novel chemical scaffold for the future development of CDK9 inhibitors.
文摘Cellular growth,development,and differentiation are tightly controlled by a conserved biological mechanism:the cell cycle.This cycle is primarily regulated by cyclin-dependent kinase(CDK)-cyclin complexes,checkpoint kinases,and CDK inhibitors.Deregulation of the cell cycle is a hallmark of the transformation of normal cells into tumor cells.Given its importance in tumorigenesis,several cell cycle inhibitors have emerged as potential therapeutic drugs for the treatment of cancers-both as singleagent therapy and in combination with traditional cytotoxic or molecular targeting agents.In this review,we discuss the mechanisms underlying cell cycle regulation and present small-molecule anticancer drugs that are under development,including both pan-CDK inhibitors and CDK4/6-selective inhibitors.In addition,we provide an outline of some promising CDK inhibitors currently in preclinical and clinical trials that target cell cycle abnormalities in various cancers.
基金financially supported by the National Natural Science Foundation of China(Nos.51873228 and 31671024)Basic Research Program of Shenzhen(No.JCYJ20180227175420974)+1 种基金Science and Technology Development Fund,Macao SAR(No.083/2017/A2)Open Research Fund of State Key Laboratory of Polymer Physics and Chemistry,Changchun Institute of Applied Chemistry,Chinese Academy of Sciences。
文摘Cyclin-dependent kinases 4 and 6 inhibitors(CDK4/6i)have been demonstrated to trigger antitumor immunity for tumor regression.However,the therapeutic performance of CDK4/6i-meadiated cancer immunotherapy was impaired by the immunosuppressive tumor microenvironment(ITM)due to overexpression of programmed death ligand 1(PD-L1)on the surface of cancer cell membrane.To improve the immunotherapeutic performance of CDK4/6i,we herein developed endosomal acidactivatable micelleplex for si RNA delivery and PD-L1 knockdown in the tumor cells in vitro and in vivo.We further demonstrated that the combination of PD-L1 knockdown and CDK4/6 inhibition facilitated intratumoral infiltration of cytotoxic T lymphocytes(CTLs),and elicited protective immune response and efficiently suppressed tumor growth in vivo.This study revealed the importance of molecular design of the micelleplex for highly efficient si RNA delivery,which might provide a novel insight for RNAi-based cancer immunotherapy.
文摘Cyclin-dependent kinase 4 and 6(CDK4/6)inhibitors combined with endocrine therapy have transformed the treatment of estrogen receptor-positive(ER+)and human epidermal growth factor receptor 2 negative(HER2-)metastatic breast cancer.However,some patients do not respond to this treatment,and patients inevitably develop resistance,such that novel biomarkers are needed to predict primary resistance,monitor treatment response for acquired resistance,and personalize treatment strategies.Circumventing the spatial and temporal limitations of tissue biopsy,newly developed liquid biopsy approaches have the potential to uncover biomarkers that can predict CDK4/6 inhibitor efficacy and resistance in breast cancer patients through a simple blood test.Studies on circulating tumor DNA(ctDNA)-based liquid biopsy biomarkers of CDK4/6 inhibitor resistance have focused primarily on genomic alterations and have failed thus far to identify clear and clinically validated predictive biomarkers,but emerging epigenetic ctDNA methodologies hold promise for further discovery.The present review outlines recent advances and future directions in ctDNA-based biomarkers of CDK4/6 inhibitor treatment response.
基金Grant support provided in part by Susan G Komen for the Cure K100575 to RSW,SME,and ADTACS-IRG 16-184-56 RSW from the American Cancer SocietyCCL-C92110 RSW and ADT from the Colorado Cancer League.
文摘Approximately 20%of invasive breast cancers have upregulation/gene amplification of the oncogene human epidermal growth factor receptor-2(HER2/ErbB2).Of these,some also express steroid receptors(the so-called Luminal B subtype),whereas others do not(the HER2 subtype).HER2 abnormal breast cancers are associated with a worse prognosis,chemotherapy resistance,and sensitivity to selected anti-HER2 targeted therapeutics.Transcriptional data from over 3000 invasive breast cancers suggest that this approach is overly simplistic;rather,the upregulation of HER2 expression resulting from gene amplification is a driver event that causes major transcriptional changes involving numerous genes and pathways in breast cancer cells.Most notably,this includes a shift from estrogenic dependence to regulatory controls driven by other nuclear receptors,particularly the androgen receptor.We discuss members of the HER receptor tyrosine kinase family,heterodimer formation,and downstream signaling,with a focus on HER2 associated pathology in breast carcinogenesis.The development and application of anti-HER2 drugs,including selected clinical trials,are discussed.In light of the many excellent reviews in the clinical literature,our emphasis is on recently developed and successful strategies to overcome targeted therapy resistance.These include combining anti-HER2 agents with programmed cell death-1 ligand or cyclin-dependent kinase 4/6 inhibitors,targeting crosstalk between HER2 and other nuclear receptors,lipid/cholesterol synthesis to inhibit receptor tyrosine kinase activation,and metformin,a broadly inhibitory drug.We seek to facilitate a better understanding of new approaches to overcome anti-HER2 drug resistance and encourage exploration of two other therapeutic interventions that may be clinically useful for HER+invasive breast cancer patients.