Triple-negative breast cancer(TNBC)represents a challenging subtype of breast cancer.High heterogeneity and lack of effective targeted therapies leave TNBC treatment a big challenge.1 However,repurposing existing drug...Triple-negative breast cancer(TNBC)represents a challenging subtype of breast cancer.High heterogeneity and lack of effective targeted therapies leave TNBC treatment a big challenge.1 However,repurposing existing drugs clinically proven to be safe and have low or no side effects is a potential choice.展开更多
Survivin(coding gene BIRC5) is a dual functional protein acting as a critical inhibitor of apoptosis(IAP) and key regulator of cell cycle progression. It is usually produced in embryonic tissues during development and...Survivin(coding gene BIRC5) is a dual functional protein acting as a critical inhibitor of apoptosis(IAP) and key regulator of cell cycle progression. It is usually produced in embryonic tissues during development and undetectable in most adult tissues.Overexpression of Survivin frequently occurs in various human cancers and increased Survivin correlates with poor clinic outcome, tumor recurrence, and therapeutic resistance. Because of its selective expression in tumor, but not normal tissues,Survivin has been recognized as an attractive target for cancer treatment. Although several therapeutic approaches targeting Survivin are actively under clinical trials in human cancers, to date no Survivin-targeted therapy has been approved for cancer treatment. Numerous studies have devoted to uncovering the underlying mechanism resulting in Survivin dysregulation at multiple levels, such as transcriptional and post-transcriptional regulation. The current article provides a literature review on the transcriptional and epigenetic regulation of Survivin expression in human cancers. We focus on the impact of DNA methylation and histone modifications, including specific lysine methylation, demethylation, and acetylation on the expression of Survivin.The latest development of epigenetic approaches targeting Survivin for cancer treatment are also discussed.展开更多
HER3 belongs to the human epidermal growth factor receptor(HER) family which also includes HER1/EGFR/erb B1,HER2/erb B2,and HER4/erb B4. As a unique member of the HER family,HER3 lacks or has little intrinsic tyrosine...HER3 belongs to the human epidermal growth factor receptor(HER) family which also includes HER1/EGFR/erb B1,HER2/erb B2,and HER4/erb B4. As a unique member of the HER family,HER3 lacks or has little intrinsic tyrosine kinase activity. It frequently co-expresses and forms heterodimers with other receptor tyrosine kinases(RTKs) in cancer cells to activate oncogenic signaling,especially the PI-3 K/Akt pathway and Src kinase. Elevated expression of HER3 has been observed in a wide variety of human cancers and associates with a worse survival in cancer patients with solid tumors.Studies on the underlying mechanism implicate HER3 expression as a major cause of treatment failure in cancer therapy. Activation of HER3 signaling has also been shown to promote cancer metastasis. These data strongly support the notion that therapeutic inactivation of HER3 and/or its downstream signaling is required to overcome treatment resistance and improve the outcomes of cancer patients.展开更多
Human epidermal growth factor receptor 3(HER3)is a unique member of the human epidermal growth factor receptor(HER/EGFR)family,since it has negligible kinase activity.Therefore,HER3 must interact with a kinase-profici...Human epidermal growth factor receptor 3(HER3)is a unique member of the human epidermal growth factor receptor(HER/EGFR)family,since it has negligible kinase activity.Therefore,HER3 must interact with a kinase-proficient receptor to form a heterodimer,leading to the activation of signaling cascades.Overexpression of HER3 is observed in various human cancers,including non-small cell lung cancer(NSCLC),and correlates with poor clinical outcomes in patients.Studies on the underlying mechanism demonstrate that HER3-initiated signaling promotes tumor metastasis and causes treatment failure in human cancers.Upregulation of HER3 is frequently observed in EGFR-mutant NSCLC treated with EGFR-tyrosine kinase inhibitors(TKIs).Increased expression of HER3 triggers the so-called EGFR-independent mechanism via interactions with other receptors to activate“by-pass signaling pathways”,thereby resulting in resistance to EGFR-TKIs.To date,no HER3-targeted therapy has been approved for cancer treatment.In both preclinical and clinical studies,targeting HER3 with a blocking an-tibody(Ab)is the only strategy being examined.Recent evaluations of an anti-HER3 Ab-drug conjugate(ADC)show promising results in patients with EGFR-TKI-resistant NSCLC.Herein,we summarize our understanding of the unique biology of HER3 in NSCLC refractory to EGFR-TKIs,with a focus on its dimerization partners and subsequent activation of signaling pathways.We also discuss the latest development of the therapeutic Abs and ADCs targeting HER3 to abrogate EGFR-TKI resistance in NSCLC.展开更多
基金approved by the Institutional Animal Care and Use Committee(IACUC)of Louisiana State University Health Sciences Center-New Orleans(LSUHSC-NO)(Protocol:4833).
文摘Triple-negative breast cancer(TNBC)represents a challenging subtype of breast cancer.High heterogeneity and lack of effective targeted therapies leave TNBC treatment a big challenge.1 However,repurposing existing drugs clinically proven to be safe and have low or no side effects is a potential choice.
基金supported by the National Institutes of Health/National Cancer Institute(NIH/NCI)(R01CA201011)the National Natural Science Foundation of China(81472763 to Bolin Liu)
文摘Survivin(coding gene BIRC5) is a dual functional protein acting as a critical inhibitor of apoptosis(IAP) and key regulator of cell cycle progression. It is usually produced in embryonic tissues during development and undetectable in most adult tissues.Overexpression of Survivin frequently occurs in various human cancers and increased Survivin correlates with poor clinic outcome, tumor recurrence, and therapeutic resistance. Because of its selective expression in tumor, but not normal tissues,Survivin has been recognized as an attractive target for cancer treatment. Although several therapeutic approaches targeting Survivin are actively under clinical trials in human cancers, to date no Survivin-targeted therapy has been approved for cancer treatment. Numerous studies have devoted to uncovering the underlying mechanism resulting in Survivin dysregulation at multiple levels, such as transcriptional and post-transcriptional regulation. The current article provides a literature review on the transcriptional and epigenetic regulation of Survivin expression in human cancers. We focus on the impact of DNA methylation and histone modifications, including specific lysine methylation, demethylation, and acetylation on the expression of Survivin.The latest development of epigenetic approaches targeting Survivin for cancer treatment are also discussed.
基金supported in part by a grant from the National Institutes of Health (NIH), USA (R01CA201011 to BL)a grant from the National Natural Science Foundation of China (81472763 to BL)
文摘HER3 belongs to the human epidermal growth factor receptor(HER) family which also includes HER1/EGFR/erb B1,HER2/erb B2,and HER4/erb B4. As a unique member of the HER family,HER3 lacks or has little intrinsic tyrosine kinase activity. It frequently co-expresses and forms heterodimers with other receptor tyrosine kinases(RTKs) in cancer cells to activate oncogenic signaling,especially the PI-3 K/Akt pathway and Src kinase. Elevated expression of HER3 has been observed in a wide variety of human cancers and associates with a worse survival in cancer patients with solid tumors.Studies on the underlying mechanism implicate HER3 expression as a major cause of treatment failure in cancer therapy. Activation of HER3 signaling has also been shown to promote cancer metastasis. These data strongly support the notion that therapeutic inactivation of HER3 and/or its downstream signaling is required to overcome treatment resistance and improve the outcomes of cancer patients.
基金We are grateful to Dr.Shi-Yong Sun(Emory University School of Medicine and Winship Cancer Institute)for his critical reading of the manuscript.This work was supported in part by a translational research grant from METAvivor Research and Support Inc.and a start-up fund provided by the Stanley S.Scott Cancer Center at Louisiana State Uni-versity(LSU)Health Sciences Center(to BL).
文摘Human epidermal growth factor receptor 3(HER3)is a unique member of the human epidermal growth factor receptor(HER/EGFR)family,since it has negligible kinase activity.Therefore,HER3 must interact with a kinase-proficient receptor to form a heterodimer,leading to the activation of signaling cascades.Overexpression of HER3 is observed in various human cancers,including non-small cell lung cancer(NSCLC),and correlates with poor clinical outcomes in patients.Studies on the underlying mechanism demonstrate that HER3-initiated signaling promotes tumor metastasis and causes treatment failure in human cancers.Upregulation of HER3 is frequently observed in EGFR-mutant NSCLC treated with EGFR-tyrosine kinase inhibitors(TKIs).Increased expression of HER3 triggers the so-called EGFR-independent mechanism via interactions with other receptors to activate“by-pass signaling pathways”,thereby resulting in resistance to EGFR-TKIs.To date,no HER3-targeted therapy has been approved for cancer treatment.In both preclinical and clinical studies,targeting HER3 with a blocking an-tibody(Ab)is the only strategy being examined.Recent evaluations of an anti-HER3 Ab-drug conjugate(ADC)show promising results in patients with EGFR-TKI-resistant NSCLC.Herein,we summarize our understanding of the unique biology of HER3 in NSCLC refractory to EGFR-TKIs,with a focus on its dimerization partners and subsequent activation of signaling pathways.We also discuss the latest development of the therapeutic Abs and ADCs targeting HER3 to abrogate EGFR-TKI resistance in NSCLC.
