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
More than 1.9 million new colorectal cancer(CRC)cases and 935000 deaths were estimated to occur worldwide in 2020,representing about one in ten cancer cases and deaths.Overall,colorectal ranks third in incidence,but s...More than 1.9 million new colorectal cancer(CRC)cases and 935000 deaths were estimated to occur worldwide in 2020,representing about one in ten cancer cases and deaths.Overall,colorectal ranks third in incidence,but second in mortality.More than half of the patients are in advanced stages at diagnosis.Treatment options are complex because of the heterogeneity of the patient population,including different molecular subtypes.Treatments have included conventional fluorouracil-based chemotherapy,targeted therapy,immunotherapy,etc.In recent years,with the development of genetic testing technology,more and more targeted drugs have been applied to the treatment of CRC,which has further prolonged the survival of metastatic CRC patients.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.
文摘More than 1.9 million new colorectal cancer(CRC)cases and 935000 deaths were estimated to occur worldwide in 2020,representing about one in ten cancer cases and deaths.Overall,colorectal ranks third in incidence,but second in mortality.More than half of the patients are in advanced stages at diagnosis.Treatment options are complex because of the heterogeneity of the patient population,including different molecular subtypes.Treatments have included conventional fluorouracil-based chemotherapy,targeted therapy,immunotherapy,etc.In recent years,with the development of genetic testing technology,more and more targeted drugs have been applied to the treatment of CRC,which has further prolonged the survival of metastatic CRC patients.
