Antibody-drug conjugates(ADCs)are antitumor drugs composed of monoclonal antibodies and cytotoxic payload covalently coupled by a linker.Currently,15 ADCs have been clinically approved worldwide.More than 100 clinical...Antibody-drug conjugates(ADCs)are antitumor drugs composed of monoclonal antibodies and cytotoxic payload covalently coupled by a linker.Currently,15 ADCs have been clinically approved worldwide.More than 100 clinical trials at different phases are underway to investigate the newly developed ADCs.ADCs represent one of the fastest growing classes of targeted antitumor drugs in oncology drug development.It takes advantage of the specific targeting of tumor-specific antigen by antibodies to deliver cytotoxic chemotherapeutic drugs precisely to tumor cells,thereby producing promising antitumor efficacy and favorable adverse effect profiles.However,emergence of drug resistance has severely hindered the clinical efficacy of ADCs.In this review,we introduce the structure and mechanism of ADCs,describe the development of ADCs,summarized the latest research about the mechanisms of ADC resistance,discussed the strategies to overcome ADCs resistance,and predicted biomarkers for treatment response to ADC,aiming to contribute to the development of ADCs in the future.展开更多
Overexpressing of ATP-binding cassette(ABC) transporters is the essential cause of multidrug resistance(MDR), which is a significant hurdle to the success of chemotherapy in many cancers.Therefore, inhibiting the acti...Overexpressing of ATP-binding cassette(ABC) transporters is the essential cause of multidrug resistance(MDR), which is a significant hurdle to the success of chemotherapy in many cancers.Therefore, inhibiting the activity of ABC transporters may be a logical approach to circumvent MDR.Olmutinib is an epidermal growth factor receptor(EGFR) tyrosine kinase inhibitor(TKI), which has been approved in South Korea for advanced EGFR T790 M-positive non-small cell lung cancer(NSCLC). Here,we found that olmutinib significantly increased the sensitivity of chemotherapy drug in ABCG2-overexpressing cells. Furthermore, olmutinib could also increase the retention of doxorubicin(DOX) and rhodamine 123(Rho 123) in ABC transporter subfamily G member 2(ABCG2)-overexpressing cells. In addition, olmutinib was found to stimulate ATPase activity and inhibit photolabeling of ABCG2 with [^(125) I]-iodoarylazidoprazosin(IAAP). However, olmutinib neither altered ABCG2 expression at protein and m RNA levels nor blocked EGFR, Her-2 downstream signaling of AKT and ERK. Importantly,olmutinib enhanced the efficacy of topotecan on the inhibition of S1-MI-80 cell xenograft growth. All the results suggest that olmutinib reverses ABCG2-mediated MDR by binding to ATP bind site of ABCG2 and increasing intracellular chemotherapeutic drug accumulation. Our findings encouraged to further clinical investigation on combination therapy of olmutinib with conventional chemotherapeutic drugs in ABCG2-overexpressing cancer patients.展开更多
Circulating tumor cells(CTCs)are precursors of distant metastasis in a subset of cancer patients.A better understanding of CTCs heterogeneity and how these CTCs survive during hematogenous dissemination could lay the ...Circulating tumor cells(CTCs)are precursors of distant metastasis in a subset of cancer patients.A better understanding of CTCs heterogeneity and how these CTCs survive during hematogenous dissemination could lay the foundation for therapeutic prevention of cancer metastasis.It remains elusive how CTCs evade immune surveillance and elimination by immune cells.In this study,we unequivocally identified a subpopulation of CTCs shielded with extracellular vesicle(EVs)-derived CD45(termed as CD45^(+)CTCs)that resisted T cell attack.A higher percentage of CD45^(+)CTCs was found to be closely correlated with higher incidence of metastasis and worse prognosis in cancer patients.Moreover,CD45^(+)tumor cells orchestrated an immunosuppressive milieu and CD45^(+)CTCs exhibited remarkably stronger metastatic potential than CD45−CTCs in vivo.Mechanistically,CD45 expressing on tumor surfaces was shown to form intercellular CD45-CD45 homophilic interactions with CD45 on T cells,thereby preventing CD45 exclusion from TCR-pMHC synapse and leading to diminished TCR signaling transduction and suppressed immune response.Together,these results pointed to an underappreciated capability of EVs-derived CD45-dressed CTCs in immune evasion and metastasis,providing a rationale for targeting EVs-derived CD45 internalization by CTCs to prevent cancer metastasis.展开更多
Hypoxia is a common phenomenon in solid tumors as the poorly organized tumor vasculature cannot fulfill the increasing oxygen demand of rapidly expanding tumors.Under hypoxia,tumor cells reshape their microenvironment...Hypoxia is a common phenomenon in solid tumors as the poorly organized tumor vasculature cannot fulfill the increasing oxygen demand of rapidly expanding tumors.Under hypoxia,tumor cells reshape their microenvironment to sustain survival,promote metastasis,and develop resistance to therapy.Exosomes are extracellular vesicles secreted by most eukaryotic cells,including tumor cells.They are enriched with a selective collection of nucleic acids and proteins from the originating cells to mediate cell-to-cell communication.Accumulating evidence suggests that exosomes derived from tumor cells play critical roles in modulating the tumor microenvironment(TME).Hypoxia is known to stimulate the secretion of exosomes from tumor cells,thereby promoting intercellular communication of hypoxic tumors with the surrounding stromal tissues.Exosome-mediated signaling pathways under hypoxic conditions have been reported to cause angiogenesis,invasion,metastasis,drug resistance,and immune escape.Recently,the programmed cell death ligand-1(PD-L1)has been reported to reside as a transmembrane protein in tumor exosomes.Exosomal PD-L1 was shown to suppress T cell effector function in the TME and cause drug resistance to immune checkpoint therapy.This review provides an update about the pivotal role of tumor-derived exosomes in drug resistance to chemotherapy and immunotherapy,particularly under hypoxic conditions.Emerging strategies that target the exosomes in the hypoxic TME to enhance the antitumor efficacy are discussed.展开更多
Competing endogenous RNAs(ceRNAs)are transcripts that possess highly similar microRNA response elements(MREs).microRNAs(miRNAs)are short,endogenous,single-stranded non-coding RNAs(ncRNAs)that can repress gene expressi...Competing endogenous RNAs(ceRNAs)are transcripts that possess highly similar microRNA response elements(MREs).microRNAs(miRNAs)are short,endogenous,single-stranded non-coding RNAs(ncRNAs)that can repress gene expression by binding to MREs on the 3’untranslated regions(UTRs)of the target mRNA transcripts to suppress gene expression by promoting mRNA degradation and/or inhibiting protein translation.mRNA transcripts,circular RNAs(circRNAs),long non-coding RNAs(lncRNAs),and transcribed pseudogenes could share similar MREs,and they can compete for the same pool of miRNAs.These ceRNAs may affect the level of one another by competing for their shared miRNAs.This interplay between different RNAs constitutes a ceRNA network,which regulates many important biological processes.Cancer drug resistance is a major factor leading to treatment failure in patients receiving chemotherapy.It can be acquired through genetic,epigenetic,and various tumor microenvironment mechanisms.The involvement of ceRNA crosstalk and its disruption in chemotherapy resistance is attracting attention in the cancer research community.This review presents an updated summary of the latest research on ceRNA dysregulation causing drug resistance across different cancer types and chemotherapeutic drug classes.Interestingly,accumulating evidence suggests that ceRNAs may be used as prognostic biomarkers to predict clinical response to cancer chemotherapy.Nevertheless,detailed experimental investigations of the putative ceRNA networks generated by computational algorithms are needed to support their translation for therapeutic and prognostic applications.展开更多
基金supported by the National Natural Science Foundation of China(Nos.U21A20421 and 82073882)the Key Project of Science Technology Program of Guangzhou(No.2023B03J0029)+1 种基金Guangdong Basic and Applied Basic Research Foundation(No.2023B1515130009)Key-Area Research and Development Program of Guangdong Province(2023B1111020005).
文摘Antibody-drug conjugates(ADCs)are antitumor drugs composed of monoclonal antibodies and cytotoxic payload covalently coupled by a linker.Currently,15 ADCs have been clinically approved worldwide.More than 100 clinical trials at different phases are underway to investigate the newly developed ADCs.ADCs represent one of the fastest growing classes of targeted antitumor drugs in oncology drug development.It takes advantage of the specific targeting of tumor-specific antigen by antibodies to deliver cytotoxic chemotherapeutic drugs precisely to tumor cells,thereby producing promising antitumor efficacy and favorable adverse effect profiles.However,emergence of drug resistance has severely hindered the clinical efficacy of ADCs.In this review,we introduce the structure and mechanism of ADCs,describe the development of ADCs,summarized the latest research about the mechanisms of ADC resistance,discussed the strategies to overcome ADCs resistance,and predicted biomarkers for treatment response to ADC,aiming to contribute to the development of ADCs in the future.
基金supported by the National Natural Science Foundation of China (No. 81473233)Guangzhou Technology Program Foundation (No. 201604020079)+1 种基金The Science and Technology Project of Guangdong Province (No. 2016A030312014)The Scientific and Technological Leading Talent Project of Guangdong Province (2015)
文摘Overexpressing of ATP-binding cassette(ABC) transporters is the essential cause of multidrug resistance(MDR), which is a significant hurdle to the success of chemotherapy in many cancers.Therefore, inhibiting the activity of ABC transporters may be a logical approach to circumvent MDR.Olmutinib is an epidermal growth factor receptor(EGFR) tyrosine kinase inhibitor(TKI), which has been approved in South Korea for advanced EGFR T790 M-positive non-small cell lung cancer(NSCLC). Here,we found that olmutinib significantly increased the sensitivity of chemotherapy drug in ABCG2-overexpressing cells. Furthermore, olmutinib could also increase the retention of doxorubicin(DOX) and rhodamine 123(Rho 123) in ABC transporter subfamily G member 2(ABCG2)-overexpressing cells. In addition, olmutinib was found to stimulate ATPase activity and inhibit photolabeling of ABCG2 with [^(125) I]-iodoarylazidoprazosin(IAAP). However, olmutinib neither altered ABCG2 expression at protein and m RNA levels nor blocked EGFR, Her-2 downstream signaling of AKT and ERK. Importantly,olmutinib enhanced the efficacy of topotecan on the inhibition of S1-MI-80 cell xenograft growth. All the results suggest that olmutinib reverses ABCG2-mediated MDR by binding to ATP bind site of ABCG2 and increasing intracellular chemotherapeutic drug accumulation. Our findings encouraged to further clinical investigation on combination therapy of olmutinib with conventional chemotherapeutic drugs in ABCG2-overexpressing cancer patients.
基金supported by the National Natural Science Foundation of China(No:U21A20421,82073882,82203649)the Key Project of Science Technology Program of Guangzhou(No:2023B03J0029)National Key R&D Program of China(No:2022YFE0209700).
文摘Circulating tumor cells(CTCs)are precursors of distant metastasis in a subset of cancer patients.A better understanding of CTCs heterogeneity and how these CTCs survive during hematogenous dissemination could lay the foundation for therapeutic prevention of cancer metastasis.It remains elusive how CTCs evade immune surveillance and elimination by immune cells.In this study,we unequivocally identified a subpopulation of CTCs shielded with extracellular vesicle(EVs)-derived CD45(termed as CD45^(+)CTCs)that resisted T cell attack.A higher percentage of CD45^(+)CTCs was found to be closely correlated with higher incidence of metastasis and worse prognosis in cancer patients.Moreover,CD45^(+)tumor cells orchestrated an immunosuppressive milieu and CD45^(+)CTCs exhibited remarkably stronger metastatic potential than CD45−CTCs in vivo.Mechanistically,CD45 expressing on tumor surfaces was shown to form intercellular CD45-CD45 homophilic interactions with CD45 on T cells,thereby preventing CD45 exclusion from TCR-pMHC synapse and leading to diminished TCR signaling transduction and suppressed immune response.Together,these results pointed to an underappreciated capability of EVs-derived CD45-dressed CTCs in immune evasion and metastasis,providing a rationale for targeting EVs-derived CD45 internalization by CTCs to prevent cancer metastasis.
基金supported in part by research grants from the Chinese University of Hong Kong(Direct Grant 2019.084&2021.010).
文摘Hypoxia is a common phenomenon in solid tumors as the poorly organized tumor vasculature cannot fulfill the increasing oxygen demand of rapidly expanding tumors.Under hypoxia,tumor cells reshape their microenvironment to sustain survival,promote metastasis,and develop resistance to therapy.Exosomes are extracellular vesicles secreted by most eukaryotic cells,including tumor cells.They are enriched with a selective collection of nucleic acids and proteins from the originating cells to mediate cell-to-cell communication.Accumulating evidence suggests that exosomes derived from tumor cells play critical roles in modulating the tumor microenvironment(TME).Hypoxia is known to stimulate the secretion of exosomes from tumor cells,thereby promoting intercellular communication of hypoxic tumors with the surrounding stromal tissues.Exosome-mediated signaling pathways under hypoxic conditions have been reported to cause angiogenesis,invasion,metastasis,drug resistance,and immune escape.Recently,the programmed cell death ligand-1(PD-L1)has been reported to reside as a transmembrane protein in tumor exosomes.Exosomal PD-L1 was shown to suppress T cell effector function in the TME and cause drug resistance to immune checkpoint therapy.This review provides an update about the pivotal role of tumor-derived exosomes in drug resistance to chemotherapy and immunotherapy,particularly under hypoxic conditions.Emerging strategies that target the exosomes in the hypoxic TME to enhance the antitumor efficacy are discussed.
基金support provided by the Chinese University of Hong Kong(Direct Grant 4054782)Guangdong-Hong Kong-Macao New Drug Screening Joint Laboratory(Project 8326200)the SKL Open Fund(SKLOF-X)from the Institute of Chinese Medicine(CUHK).
文摘Competing endogenous RNAs(ceRNAs)are transcripts that possess highly similar microRNA response elements(MREs).microRNAs(miRNAs)are short,endogenous,single-stranded non-coding RNAs(ncRNAs)that can repress gene expression by binding to MREs on the 3’untranslated regions(UTRs)of the target mRNA transcripts to suppress gene expression by promoting mRNA degradation and/or inhibiting protein translation.mRNA transcripts,circular RNAs(circRNAs),long non-coding RNAs(lncRNAs),and transcribed pseudogenes could share similar MREs,and they can compete for the same pool of miRNAs.These ceRNAs may affect the level of one another by competing for their shared miRNAs.This interplay between different RNAs constitutes a ceRNA network,which regulates many important biological processes.Cancer drug resistance is a major factor leading to treatment failure in patients receiving chemotherapy.It can be acquired through genetic,epigenetic,and various tumor microenvironment mechanisms.The involvement of ceRNA crosstalk and its disruption in chemotherapy resistance is attracting attention in the cancer research community.This review presents an updated summary of the latest research on ceRNA dysregulation causing drug resistance across different cancer types and chemotherapeutic drug classes.Interestingly,accumulating evidence suggests that ceRNAs may be used as prognostic biomarkers to predict clinical response to cancer chemotherapy.Nevertheless,detailed experimental investigations of the putative ceRNA networks generated by computational algorithms are needed to support their translation for therapeutic and prognostic applications.
