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Advances of Targeted Therapy in Treatment of Unresectable Metastatic Colorectal Cancer.

Lee SY, Oh SC - Biomed Res Int (2016)

Bottom Line: Development and introduction of biologic agents in treatment of patients with metastatic CRC have brought improved outcomes.Monoclonal antibodies directing epidermal growth factor receptors and vascular endothelial growth factor are main biologic agents currently used in treatment of metastatic CRC.Here, we introduce mechanisms of action of the biologic agents currently used for treatment of metastatic CRC and several landmark historical clinical studies which have changed the main stream of treatment.

View Article: PubMed Central - PubMed

Affiliation: Division of Oncology/Hematology, Department of Internal Medicine, College of Medicine, Korea University, 148 Gurodong-ro, Guro-gu, Seoul 08308, Republic of Korea.

ABSTRACT
Despite being one of the most frequently diagnosed cancers worldwide, prognosis of metastatic colorectal cancer (CRC) was poor. Development and introduction of biologic agents in treatment of patients with metastatic CRC have brought improved outcomes. Monoclonal antibodies directing epidermal growth factor receptors and vascular endothelial growth factor are main biologic agents currently used in treatment of metastatic CRC. Encouraged by results from many clinical trials demonstrating efficacy of those monoclonal antibodies, the combination therapy with those targeted agents and conventional chemotherapeutic agents has been established as the standard therapy for patients with metastatic CRC. However, emergency of resistance to those target agents has limited the efficacy of treatment, and strategies to overcome the resistance are now being investigated by newly developed biological techniques clarifying how to acquire resistance. Here, we introduce mechanisms of action of the biologic agents currently used for treatment of metastatic CRC and several landmark historical clinical studies which have changed the main stream of treatment. The mechanism of resistance to those agents, one of serious problems in treatment metastatic CRC, and ongoing clinical trials to overcome the limitations and improve treatment outcomes will also be presented in this review.

No MeSH data available.


Related in: MedlinePlus

Signaling through EGFR. Signaling is initiated by interaction of ligands with EGFR. The resultant autophosphorylation of tyrosine kinase residues binds to the growth-factor-receptor-bound protein 2 (GRB2), and SOS is recruited to the plasma membrane. Subsequent activation of RAS activates RAS-RAF-MEK-MAPKs pathway. PI3Ks-AKT or RAS-PLCε-PKC are also known to be activated by signaling through EGFR. TM: transmembrane.
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fig1: Signaling through EGFR. Signaling is initiated by interaction of ligands with EGFR. The resultant autophosphorylation of tyrosine kinase residues binds to the growth-factor-receptor-bound protein 2 (GRB2), and SOS is recruited to the plasma membrane. Subsequent activation of RAS activates RAS-RAF-MEK-MAPKs pathway. PI3Ks-AKT or RAS-PLCε-PKC are also known to be activated by signaling through EGFR. TM: transmembrane.

Mentions: The ERBB family of receptors consist of 4 members, EGFR and EGFR-related receptors (HER2, HER3, and HER4). EGFR, a receptor tyrosine kinase (RTK), is ubiquitously expressed in epithelial, mesenchymal, and neuronal cells and play a role in development, proliferation, and differentiation [8]. The ERBB family of RTKs are transmembrane receptors consisting of an extracellular domain, a single hydrophobic transmembrane segment, and an intracellular domain containing a preserved tyrosine kinase residue [9]. The signaling through the EGFR is initiated with binding of ligands to domains I and III of extracellular domain, the binding site of the receptor. The binding of ligands induces formation of heterodimer or homodimer between the receptor family members leading to autophosphorylation of tyrosine kinase residue in the carboxy-terminus of the receptor protein. The autophosphorylated receptors subsequently activate downstream intracellular signaling pathways such as RAS-RAF-mitogen-activated protein kinase kinase- (MEK-) mitogen-activated protein kinase (MAPKs), or phosphatidylinositol 3-kinase- (PI3K-) AKT pathway. Other than these pathways, phospholipase C- (PLCγ-) protein serine/threonine kinase C (PKC) pathway is also known to be activated by EGFR [10–13] (Figure 1).


Advances of Targeted Therapy in Treatment of Unresectable Metastatic Colorectal Cancer.

Lee SY, Oh SC - Biomed Res Int (2016)

Signaling through EGFR. Signaling is initiated by interaction of ligands with EGFR. The resultant autophosphorylation of tyrosine kinase residues binds to the growth-factor-receptor-bound protein 2 (GRB2), and SOS is recruited to the plasma membrane. Subsequent activation of RAS activates RAS-RAF-MEK-MAPKs pathway. PI3Ks-AKT or RAS-PLCε-PKC are also known to be activated by signaling through EGFR. TM: transmembrane.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4835624&req=5

fig1: Signaling through EGFR. Signaling is initiated by interaction of ligands with EGFR. The resultant autophosphorylation of tyrosine kinase residues binds to the growth-factor-receptor-bound protein 2 (GRB2), and SOS is recruited to the plasma membrane. Subsequent activation of RAS activates RAS-RAF-MEK-MAPKs pathway. PI3Ks-AKT or RAS-PLCε-PKC are also known to be activated by signaling through EGFR. TM: transmembrane.
Mentions: The ERBB family of receptors consist of 4 members, EGFR and EGFR-related receptors (HER2, HER3, and HER4). EGFR, a receptor tyrosine kinase (RTK), is ubiquitously expressed in epithelial, mesenchymal, and neuronal cells and play a role in development, proliferation, and differentiation [8]. The ERBB family of RTKs are transmembrane receptors consisting of an extracellular domain, a single hydrophobic transmembrane segment, and an intracellular domain containing a preserved tyrosine kinase residue [9]. The signaling through the EGFR is initiated with binding of ligands to domains I and III of extracellular domain, the binding site of the receptor. The binding of ligands induces formation of heterodimer or homodimer between the receptor family members leading to autophosphorylation of tyrosine kinase residue in the carboxy-terminus of the receptor protein. The autophosphorylated receptors subsequently activate downstream intracellular signaling pathways such as RAS-RAF-mitogen-activated protein kinase kinase- (MEK-) mitogen-activated protein kinase (MAPKs), or phosphatidylinositol 3-kinase- (PI3K-) AKT pathway. Other than these pathways, phospholipase C- (PLCγ-) protein serine/threonine kinase C (PKC) pathway is also known to be activated by EGFR [10–13] (Figure 1).

Bottom Line: Development and introduction of biologic agents in treatment of patients with metastatic CRC have brought improved outcomes.Monoclonal antibodies directing epidermal growth factor receptors and vascular endothelial growth factor are main biologic agents currently used in treatment of metastatic CRC.Here, we introduce mechanisms of action of the biologic agents currently used for treatment of metastatic CRC and several landmark historical clinical studies which have changed the main stream of treatment.

View Article: PubMed Central - PubMed

Affiliation: Division of Oncology/Hematology, Department of Internal Medicine, College of Medicine, Korea University, 148 Gurodong-ro, Guro-gu, Seoul 08308, Republic of Korea.

ABSTRACT
Despite being one of the most frequently diagnosed cancers worldwide, prognosis of metastatic colorectal cancer (CRC) was poor. Development and introduction of biologic agents in treatment of patients with metastatic CRC have brought improved outcomes. Monoclonal antibodies directing epidermal growth factor receptors and vascular endothelial growth factor are main biologic agents currently used in treatment of metastatic CRC. Encouraged by results from many clinical trials demonstrating efficacy of those monoclonal antibodies, the combination therapy with those targeted agents and conventional chemotherapeutic agents has been established as the standard therapy for patients with metastatic CRC. However, emergency of resistance to those target agents has limited the efficacy of treatment, and strategies to overcome the resistance are now being investigated by newly developed biological techniques clarifying how to acquire resistance. Here, we introduce mechanisms of action of the biologic agents currently used for treatment of metastatic CRC and several landmark historical clinical studies which have changed the main stream of treatment. The mechanism of resistance to those agents, one of serious problems in treatment metastatic CRC, and ongoing clinical trials to overcome the limitations and improve treatment outcomes will also be presented in this review.

No MeSH data available.


Related in: MedlinePlus