Breast cancer,a predominant global health issue,requires ongoing exploration of new therapeutic strategies.Palbociclib(PAL),a well-known cyclin-dependent kinase(CDK)inhibitor,plays a critical role in breast cancer tre...Breast cancer,a predominant global health issue,requires ongoing exploration of new therapeutic strategies.Palbociclib(PAL),a well-known cyclin-dependent kinase(CDK)inhibitor,plays a critical role in breast cancer treatment.While its efficacy is recognized,the interplay between PAL and cellular autophagy,particularly in the context of the RAF/MEK/ERK signaling pathway,remains insufficiently explored.This study investigates PAL’s inhibitory effects on breast cancer using both in vitro(MCF7 and MDA-MB-468 cells)and in vivo(tumor-bearing nude mice)models.Aimed at elucidating the impact of PAL on autophagic processes and exploring the potential of combining it with trametinib(TRA),an MEK inhibitor,our research seeks to address the challenge of PAL-induced drug resistance.Ourfindings reveal that PAL significantly decreases the viability of MCF7 and MDA-MB-468 cells and reduces tumor size in mice while showing minimal cytotoxicity in MCF10A cells.However,PAL also induces protective autophagy,potentially leading to drug resistance via the RAF/MEK/ERK pathway activation.Introducing TRA effectively neutralized this autophagy,enhancing PAL’s anti-tumor efficacy.A combination of PAL and TRA synergistically reduced cell viability and proliferation,and in vivo studies showed notable tumor size reduction.In conclusion,the PAL and TRA combination emerges as a promising strategy for overcoming PAL-induced resistance,offering a new horizon in breast cancer treatment.展开更多
Objective: Lack of effective therapies remains a problem in the treatment of oral squamous cell carcinoma(OSCC), especially in patients with advanced tumors. OSCC development is driven by multiple aberrancies within t...Objective: Lack of effective therapies remains a problem in the treatment of oral squamous cell carcinoma(OSCC), especially in patients with advanced tumors. OSCC development is driven by multiple aberrancies within the cell cycle pathway, including amplification of cyclin D1 and loss of p16. Hence, cell cycle inhibitors of the CDK4/6-cyclin D axis are appealing targets for OSCC treatment. Here, we determined the potency of palbociclib and identified genetic features that are associated with the response of palbociclib in OSCC.Methods: The effect of palbociclib was evaluated in a panel of well-characterized OSCC cell lines by cell proliferation assays and further confirmed by in vivo evaluation in xenograft models. PIK3CA-mutant isogenic cell lines were used to investigate the effect of PIK3CA mutation towards palbociclib response.Results: We demonstrated that 80% of OSCC cell lines are sensitive to palbociclib at sub-micromolar concentrations.Consistently, palbociclib was effective in controlling tumor growth in mice. We identified that palbociclib-resistant cells harbored mutations in PIK3CA. Using isogenic cell lines, we showed that PIK3CA mutant cells are less responsive to palbociclib as compared to wild-type cells with concurrent upregulation of CDK2 and cyclin E1 protein levels. We further demonstrated that the combination of a PI3 K/mTOR inhibitor(PF-04691502) and palbociclib completely controlled tumor growth in mice.Conclusions: This study demonstrated the potency of palbociclib in OSCC models and provides a rationale for the inclusion of PIK3CA testing in the clinical evaluation of CDK4/6 inhibitors and suggests combination approaches for further clinical studies.展开更多
Objective:Natural extracts,including nobiletin,have been reported to enhance the efficacy and sensitivity of chemotherapeutic drugs.However,whether and how nobiletin affects tumor growth and progression in renal cell ...Objective:Natural extracts,including nobiletin,have been reported to enhance the efficacy and sensitivity of chemotherapeutic drugs.However,whether and how nobiletin affects tumor growth and progression in renal cell carcinoma(RCC)are still unclear.Methods:Cell proliferation,cell cycle and apoptosis analyses,colony-formation assays,immunoblotting analysis,and q RT-PCR analysis were performed to investigate how nobiletin affected RCC cell proliferation in vitro.The nude mouse model was used to test the efficacy of nobiletin alone or in combination with palbociclib.Results:Nobiletin inhibited cell proliferation by inducing G1 cell cycle arrest and cell apoptosis in RCC cells.Mechanistically,nobiletin decreased SKP2 protein expression by reducing its transcriptional level.The downregulated SKP2 caused accumulation of its substrates,p27 and p21,which further inhibited the activity of the G1 phase-related protein,CDK2,leading to inhibition of cell proliferation and tumor formation.A higher SKP2 protein level indicated less sensitivity to the CDK4/6 inhibitor,palbociclib.A combination of nobiletin and palbociclib showed a synergistic tumor inhibition in vitro and in an in vivo model.Conclusions:Nobiletin downregulated the SKP2-p21/p27-CDK2 axis to inhibit tumor progression and showed synergistic tumor inhibition effects with the CDK4/6 inhibitor,palbociclib,on RCC,which indicates a potential new therapeutic strategy.展开更多
As a specific cyclin-dependent kinase 4/6 inhibitor,palbociclibimproved the prognosis in patients with hormone receptor-positive and human epidermal growth factor receptor-2 negative breast cancer.Emerging data showed...As a specific cyclin-dependent kinase 4/6 inhibitor,palbociclibimproved the prognosis in patients with hormone receptor-positive and human epidermal growth factor receptor-2 negative breast cancer.Emerging data showed that palbociclib shed a new therapeutic regimen forbreast cancers and playsan essentialmilestone in the development of anti-tumor drugs,especially for advanced breast cancer.In this minireview,we aimed to summarize the mechanism,clinical application,and side effectsof palbociclib.展开更多
Cyclin-dependent kinase inhibitor 2A/2B(CDKN2A/2B)deletions are frequently identified in patients with biliary tract cancer;however,standard treatment options for this genetic alteration are lacking.Here,we present th...Cyclin-dependent kinase inhibitor 2A/2B(CDKN2A/2B)deletions are frequently identified in patients with biliary tract cancer;however,standard treatment options for this genetic alteration are lacking.Here,we present the case of a 64-year-old woman diagnosed with intrahepatic cholangiocarcinoma and hilar lymph node metastasis who underwent radical surgery.Postoperative pathology confirmed moderately differentiated adenocarcinoma.The tumor recurred during the second cycle of adjuvant chemotherapy following surgery,and the metastatic sites included the cranial region,right lung,and right adrenal gland.Genetic analysis revealed a CDKN2A/2B deletion,indicating palbociclib sensitivity.Subsequently,the patient received palbociclib plus lenvatinib as systemic therapy,along with stereotactic radiotherapy for the intracranial lesion.Notably,the right pulmonary metastasis significantly regressed after 12 months of treatment,with the complete disappearance of the intracranial tumor.However,the disease progressed at 32.2 months,with significant enlargement of the right adrenal gland metastasis and new metastasis in the right lung.The progression-free survival and overall survival were 32.2 months and 34.4 months,respectively.In conclusion,our case demonstrates that palbociclib plus lenvatinib is a promising chemotherapy-free second-line treatment for intrahepatic cholangiocarcinoma with a CDKN2A/2B deletion.展开更多
Metastatic hormone receptor-positive(HR+),human epidermal growth factor receptor 2-negative(HER2−)breast cancer often develops resistance to first-line treatment,typically combining cyclin-dependent kinase 4 and 6 inh...Metastatic hormone receptor-positive(HR+),human epidermal growth factor receptor 2-negative(HER2−)breast cancer often develops resistance to first-line treatment,typically combining cyclin-dependent kinase 4 and 6 inhibitors(CDK4/6i)with hormone therapy(HT)[1,2].After an initial response,most patients become resistant,and compensatory mechanisms are not fully uncovered[3].展开更多
基金supported by the Sichuan Science and Technology Program(Grant Nos.2020YJ0494,24GJHZ0058,21RCYJ0021,and 2022YFS0620)the National Natural Science Foundation of China(Grant No.81903829)+1 种基金the Southwest Medical University Science and Technology Program(Grant Nos.2021ZKZD015,2021ZKZD018,and 2021ZKMS046)the Macao Science and Technology Development Fund of Macao SAR(Project Nos.SKLQRCM(MUST)-2020-2022 and MUST-SKL-2021-005).
文摘Breast cancer,a predominant global health issue,requires ongoing exploration of new therapeutic strategies.Palbociclib(PAL),a well-known cyclin-dependent kinase(CDK)inhibitor,plays a critical role in breast cancer treatment.While its efficacy is recognized,the interplay between PAL and cellular autophagy,particularly in the context of the RAF/MEK/ERK signaling pathway,remains insufficiently explored.This study investigates PAL’s inhibitory effects on breast cancer using both in vitro(MCF7 and MDA-MB-468 cells)and in vivo(tumor-bearing nude mice)models.Aimed at elucidating the impact of PAL on autophagic processes and exploring the potential of combining it with trametinib(TRA),an MEK inhibitor,our research seeks to address the challenge of PAL-induced drug resistance.Ourfindings reveal that PAL significantly decreases the viability of MCF7 and MDA-MB-468 cells and reduces tumor size in mice while showing minimal cytotoxicity in MCF10A cells.However,PAL also induces protective autophagy,potentially leading to drug resistance via the RAF/MEK/ERK pathway activation.Introducing TRA effectively neutralized this autophagy,enhancing PAL’s anti-tumor efficacy.A combination of PAL and TRA synergistically reduced cell viability and proliferation,and in vivo studies showed notable tumor size reduction.In conclusion,the PAL and TRA combination emerges as a promising strategy for overcoming PAL-induced resistance,offering a new horizon in breast cancer treatment.
基金supported by a grant from High Impact Research, Ministry of Higher Education (HIR-MOHE) from University of Malaya (Grant No. UM.C/625/1/HIR/MOHE/ DENT-03)Cancer Research Malaysia
文摘Objective: Lack of effective therapies remains a problem in the treatment of oral squamous cell carcinoma(OSCC), especially in patients with advanced tumors. OSCC development is driven by multiple aberrancies within the cell cycle pathway, including amplification of cyclin D1 and loss of p16. Hence, cell cycle inhibitors of the CDK4/6-cyclin D axis are appealing targets for OSCC treatment. Here, we determined the potency of palbociclib and identified genetic features that are associated with the response of palbociclib in OSCC.Methods: The effect of palbociclib was evaluated in a panel of well-characterized OSCC cell lines by cell proliferation assays and further confirmed by in vivo evaluation in xenograft models. PIK3CA-mutant isogenic cell lines were used to investigate the effect of PIK3CA mutation towards palbociclib response.Results: We demonstrated that 80% of OSCC cell lines are sensitive to palbociclib at sub-micromolar concentrations.Consistently, palbociclib was effective in controlling tumor growth in mice. We identified that palbociclib-resistant cells harbored mutations in PIK3CA. Using isogenic cell lines, we showed that PIK3CA mutant cells are less responsive to palbociclib as compared to wild-type cells with concurrent upregulation of CDK2 and cyclin E1 protein levels. We further demonstrated that the combination of a PI3 K/mTOR inhibitor(PF-04691502) and palbociclib completely controlled tumor growth in mice.Conclusions: This study demonstrated the potency of palbociclib in OSCC models and provides a rationale for the inclusion of PIK3CA testing in the clinical evaluation of CDK4/6 inhibitors and suggests combination approaches for further clinical studies.
基金supported by the National Natural Science Foundation of China(Grant Nos.81772702 and 81502214)。
文摘Objective:Natural extracts,including nobiletin,have been reported to enhance the efficacy and sensitivity of chemotherapeutic drugs.However,whether and how nobiletin affects tumor growth and progression in renal cell carcinoma(RCC)are still unclear.Methods:Cell proliferation,cell cycle and apoptosis analyses,colony-formation assays,immunoblotting analysis,and q RT-PCR analysis were performed to investigate how nobiletin affected RCC cell proliferation in vitro.The nude mouse model was used to test the efficacy of nobiletin alone or in combination with palbociclib.Results:Nobiletin inhibited cell proliferation by inducing G1 cell cycle arrest and cell apoptosis in RCC cells.Mechanistically,nobiletin decreased SKP2 protein expression by reducing its transcriptional level.The downregulated SKP2 caused accumulation of its substrates,p27 and p21,which further inhibited the activity of the G1 phase-related protein,CDK2,leading to inhibition of cell proliferation and tumor formation.A higher SKP2 protein level indicated less sensitivity to the CDK4/6 inhibitor,palbociclib.A combination of nobiletin and palbociclib showed a synergistic tumor inhibition in vitro and in an in vivo model.Conclusions:Nobiletin downregulated the SKP2-p21/p27-CDK2 axis to inhibit tumor progression and showed synergistic tumor inhibition effects with the CDK4/6 inhibitor,palbociclib,on RCC,which indicates a potential new therapeutic strategy.
文摘As a specific cyclin-dependent kinase 4/6 inhibitor,palbociclibimproved the prognosis in patients with hormone receptor-positive and human epidermal growth factor receptor-2 negative breast cancer.Emerging data showed that palbociclib shed a new therapeutic regimen forbreast cancers and playsan essentialmilestone in the development of anti-tumor drugs,especially for advanced breast cancer.In this minireview,we aimed to summarize the mechanism,clinical application,and side effectsof palbociclib.
基金funded by the National High-Level Hospital Clinical Research Funding[2022-PUMCH-B-128]CAMS Innovation Fund for Medical Sciences([2022-I2M-C&T-A-003],[2021-I2M-1-061])+3 种基金CSCO-Hengrui Cancer Research Fund([Y-HR2019-0239])CSCO-MSD Cancer Research Fund[YMSDZD2021-0213]the National Ten-thousand Talent Program.LZ is supported by the National Natural Science Foundation of China(No.81960125)the Department of Science and Technology of Guizhou Province(No.Qiankehe Foundation[2020]1Y302).
文摘Cyclin-dependent kinase inhibitor 2A/2B(CDKN2A/2B)deletions are frequently identified in patients with biliary tract cancer;however,standard treatment options for this genetic alteration are lacking.Here,we present the case of a 64-year-old woman diagnosed with intrahepatic cholangiocarcinoma and hilar lymph node metastasis who underwent radical surgery.Postoperative pathology confirmed moderately differentiated adenocarcinoma.The tumor recurred during the second cycle of adjuvant chemotherapy following surgery,and the metastatic sites included the cranial region,right lung,and right adrenal gland.Genetic analysis revealed a CDKN2A/2B deletion,indicating palbociclib sensitivity.Subsequently,the patient received palbociclib plus lenvatinib as systemic therapy,along with stereotactic radiotherapy for the intracranial lesion.Notably,the right pulmonary metastasis significantly regressed after 12 months of treatment,with the complete disappearance of the intracranial tumor.However,the disease progressed at 32.2 months,with significant enlargement of the right adrenal gland metastasis and new metastasis in the right lung.The progression-free survival and overall survival were 32.2 months and 34.4 months,respectively.In conclusion,our case demonstrates that palbociclib plus lenvatinib is a promising chemotherapy-free second-line treatment for intrahepatic cholangiocarcinoma with a CDKN2A/2B deletion.
基金supported by grants fromthe National Fund for Scientific Research(NFSR-FNRS)Belgium(NES:PDR T.023020,CDR J.0178.22)the credit sectorial of the University of Liege(NES:FSR-S-SS-22/61,FSR-S-SS-22/64)the Foundation Contre le Cancer,Belgium(NES and AN:FCC-2022-181).
文摘Metastatic hormone receptor-positive(HR+),human epidermal growth factor receptor 2-negative(HER2−)breast cancer often develops resistance to first-line treatment,typically combining cyclin-dependent kinase 4 and 6 inhibitors(CDK4/6i)with hormone therapy(HT)[1,2].After an initial response,most patients become resistant,and compensatory mechanisms are not fully uncovered[3].
