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
Ovarian cancer is the second most lethal gynecological cancer worldwide and while most patients respond to initial therapy, they often relapse with resistant disease. Human epidermal growth factor receptors(especially...Ovarian cancer is the second most lethal gynecological cancer worldwide and while most patients respond to initial therapy, they often relapse with resistant disease. Human epidermal growth factor receptors(especially HER1/EGFR and HER2/ERBB2) are involved in disease progression; hence, strategies to inhibit their action could prove advantageous in ovarian cancer patients,especially in patients resistant to first line therapy. Monoclonal antibodies and tyrosine kinase inhibitors are two classes of drugs that act on these receptors. They have demonstrated valuable antitumor activity in multiple cancers and their possible use in ovarian cancer continues to be studied. In this review, we discuss the human epidermal growth factor receptor family; review emerging clinical studies on monoclonal antibodies and tyrosine kinase inhibitors targeting these receptors in ovarian cancer patients; and propose future research possibilities in this area.展开更多
The limited efficacy of conventional cytotoxic treatment regimes for advanced gastrointestinal neuroendocrine cancers emphasizes the need for novel and more effective medical treatment options. Recent findings on the ...The limited efficacy of conventional cytotoxic treatment regimes for advanced gastrointestinal neuroendocrine cancers emphasizes the need for novel and more effective medical treatment options. Recent findings on the specific biological features of this family of neoplasms has led to the development of new targeted therapies, which take into account the high vascularization and abundant expression of specific growth factors and cognate tyrosine kinase receptors. This review will briefly summarize the status and future perspectives of antiangiogenic, mTOR- or growth factor receptor-based pharmacological approaches for the innovative treatment of gastrointestinal neuroendocrine tumors. In view of the multitude of novel targeted approaches, the rationale for innovative combination therapies, i.e. combining growth factor (receptor)-targeting agents with chemo- or biotherapeutics or with other novel anticancer drugs such as HDAC or proteasome inhibitors will be taken into account.展开更多
Colorectal cancer constitutes one of the most common malignancies and the second leading cause of death from cancer in the western world representing one million new cases and half a million deaths annually worldwide....Colorectal cancer constitutes one of the most common malignancies and the second leading cause of death from cancer in the western world representing one million new cases and half a million deaths annually worldwide. The treatment of patients with metastatic colon cancer comprises different regimens of chemotherapeutic compounds （fluoropyrimidines, irinotecan and oxaliplatin） and new targeted therapies. Interestingly, most recent trials that attempt to expose patients to all five-drug classes （fluoropyrimidines, irinotecan, oxaliplatin, bevacizumab and cetuximab） achieve an overall survival well over 2 years. In this review we will focus on the main epidermal growth factor receptor inhibitors demonstrating clinical benefit for colorectal cancer mainly cetuximab, panitumumab, erlotinib and gefltinib. We will also describe briefly the molecular steps that lie beneath them and the different clinical or molecular mechanisms that are reported for resistance and response.展开更多
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.
基金The work disclosed in this publication is partially funded by the Endeavour Scholarship Scheme (Malta) Scholarships are part-financed by the European Union–European Social Fund (ESF)–Operational Program II–Cohesion Policy 2014–2020 "Investing in human capital to create more opportunities and promote the well-being of society"
文摘Ovarian cancer is the second most lethal gynecological cancer worldwide and while most patients respond to initial therapy, they often relapse with resistant disease. Human epidermal growth factor receptors(especially HER1/EGFR and HER2/ERBB2) are involved in disease progression; hence, strategies to inhibit their action could prove advantageous in ovarian cancer patients,especially in patients resistant to first line therapy. Monoclonal antibodies and tyrosine kinase inhibitors are two classes of drugs that act on these receptors. They have demonstrated valuable antitumor activity in multiple cancers and their possible use in ovarian cancer continues to be studied. In this review, we discuss the human epidermal growth factor receptor family; review emerging clinical studies on monoclonal antibodies and tyrosine kinase inhibitors targeting these receptors in ovarian cancer patients; and propose future research possibilities in this area.
文摘The limited efficacy of conventional cytotoxic treatment regimes for advanced gastrointestinal neuroendocrine cancers emphasizes the need for novel and more effective medical treatment options. Recent findings on the specific biological features of this family of neoplasms has led to the development of new targeted therapies, which take into account the high vascularization and abundant expression of specific growth factors and cognate tyrosine kinase receptors. This review will briefly summarize the status and future perspectives of antiangiogenic, mTOR- or growth factor receptor-based pharmacological approaches for the innovative treatment of gastrointestinal neuroendocrine tumors. In view of the multitude of novel targeted approaches, the rationale for innovative combination therapies, i.e. combining growth factor (receptor)-targeting agents with chemo- or biotherapeutics or with other novel anticancer drugs such as HDAC or proteasome inhibitors will be taken into account.
文摘Colorectal cancer constitutes one of the most common malignancies and the second leading cause of death from cancer in the western world representing one million new cases and half a million deaths annually worldwide. The treatment of patients with metastatic colon cancer comprises different regimens of chemotherapeutic compounds （fluoropyrimidines, irinotecan and oxaliplatin） and new targeted therapies. Interestingly, most recent trials that attempt to expose patients to all five-drug classes （fluoropyrimidines, irinotecan, oxaliplatin, bevacizumab and cetuximab） achieve an overall survival well over 2 years. In this review we will focus on the main epidermal growth factor receptor inhibitors demonstrating clinical benefit for colorectal cancer mainly cetuximab, panitumumab, erlotinib and gefltinib. We will also describe briefly the molecular steps that lie beneath them and the different clinical or molecular mechanisms that are reported for resistance and response.
