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The Potential of panHER Inhibition in Cancer.

Wang X, Batty KM, Crowe PJ, Goldstein D, Yang JL - Front Oncol (2015)

Bottom Line: Hyper-activation of the HER (erbB) family receptors, HER 1-4, leads to up-regulation of the three vital signaling pathways: mitogen activated protein kinase, phosphoinositide 3-kinase/AKT, and Janus kinase/signal transducer and activator of transcription pathways.The emergence of an anti-panHER approach to blockade of these pathways as a cancer treatment may provide a solution to this resistance.Recent literature associated with HER signaling pathways and panHER inhibition was reviewed through PubMed and Medline database, followed by critical comparison and analysis.

View Article: PubMed Central - PubMed

Affiliation: Sarcoma Nano-Oncology Group, Adult Cancer Program, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales (UNSW) , Sydney, NSW , Australia ; Department of Surgery, Prince of Wales Clinical School, University of New South Wales (UNSW) , Sydney, NSW , Australia.

ABSTRACT

Purpose: Hyper-activation of the HER (erbB) family receptors, HER 1-4, leads to up-regulation of the three vital signaling pathways: mitogen activated protein kinase, phosphoinositide 3-kinase/AKT, and Janus kinase/signal transducer and activator of transcription pathways. Blocking HER1/EGFR has a limited anticancer effect due to either secondary mutation e.g., T790M or by-pass signaling of other HER members. The emergence of an anti-panHER approach to blockade of these pathways as a cancer treatment may provide a solution to this resistance. This review aimed to provide an overview of the HER signaling pathways and their involvement in tumor progression and examine the current progress in panHER inhibition.

Methods: Recent literature associated with HER signaling pathways and panHER inhibition was reviewed through PubMed and Medline database, followed by critical comparison and analysis.

Results: Pre-clinical studies and clinical trials of panHER inhibitors show promising results, and the potential to improve patient outcomes in solid cancers.

Conclusion:  The use of panHER inhibitors in cancers with HER-family hyper-activation, such as other epithelial cancers and sarcoma, is a new direction to research and has potential in clinical cancer therapy in the future.

No MeSH data available.


Related in: MedlinePlus

Signal transduction by HER-family. This figure summarizes the interplay between three pathways: MAPK, P13K/AKT, and JAK/STAT. MAPK dramatically enhances transcriptional activation by STAT (11). EGFR/HER1 cannot directly activate the P13K/AKT pathway (12), but it couples to the ras/MAPK pathway as well as to the ras/PI3K/AKT pathway (10). This interplay of pathways forms the source of by-pass resistance to EGFR TKIs. TKD, tyrosine kinase domain; MEK, mitogen activated protein kinase kinase; MAPK, mitogen activated protein kinase; PI3K, phosphoinositide 3-kinase; mTOR, mammalian target of rapamycin; JAK, janus kinase; STAT, signal transducer and activator of transcription.
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Figure 1: Signal transduction by HER-family. This figure summarizes the interplay between three pathways: MAPK, P13K/AKT, and JAK/STAT. MAPK dramatically enhances transcriptional activation by STAT (11). EGFR/HER1 cannot directly activate the P13K/AKT pathway (12), but it couples to the ras/MAPK pathway as well as to the ras/PI3K/AKT pathway (10). This interplay of pathways forms the source of by-pass resistance to EGFR TKIs. TKD, tyrosine kinase domain; MEK, mitogen activated protein kinase kinase; MAPK, mitogen activated protein kinase; PI3K, phosphoinositide 3-kinase; mTOR, mammalian target of rapamycin; JAK, janus kinase; STAT, signal transducer and activator of transcription.

Mentions: The HER receptors are composed of a large extra-cellular ligand-binding domain, which has four subdomains (I–IV), followed by a transmembrane domain, a small intracellular juxtamembrane domain preceding the kinase domain, and a C-terminal tail, on which the docking sites for phosphotyrosine-binding effector molecules are found (10). These four receptors form homo-dimers and hetero-dimers, which are associated with instigation of different downstream pathways. Emerging targeted treatment has focused on inhibition of these HER receptors via either external monoclonal antibodies (mAb) or small molecule tyrosine kinase inhibitors (TKIs). Figure 1 presents a simplified summary of the HER signaling pathways.


The Potential of panHER Inhibition in Cancer.

Wang X, Batty KM, Crowe PJ, Goldstein D, Yang JL - Front Oncol (2015)

Signal transduction by HER-family. This figure summarizes the interplay between three pathways: MAPK, P13K/AKT, and JAK/STAT. MAPK dramatically enhances transcriptional activation by STAT (11). EGFR/HER1 cannot directly activate the P13K/AKT pathway (12), but it couples to the ras/MAPK pathway as well as to the ras/PI3K/AKT pathway (10). This interplay of pathways forms the source of by-pass resistance to EGFR TKIs. TKD, tyrosine kinase domain; MEK, mitogen activated protein kinase kinase; MAPK, mitogen activated protein kinase; PI3K, phosphoinositide 3-kinase; mTOR, mammalian target of rapamycin; JAK, janus kinase; STAT, signal transducer and activator of transcription.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4309158&req=5

Figure 1: Signal transduction by HER-family. This figure summarizes the interplay between three pathways: MAPK, P13K/AKT, and JAK/STAT. MAPK dramatically enhances transcriptional activation by STAT (11). EGFR/HER1 cannot directly activate the P13K/AKT pathway (12), but it couples to the ras/MAPK pathway as well as to the ras/PI3K/AKT pathway (10). This interplay of pathways forms the source of by-pass resistance to EGFR TKIs. TKD, tyrosine kinase domain; MEK, mitogen activated protein kinase kinase; MAPK, mitogen activated protein kinase; PI3K, phosphoinositide 3-kinase; mTOR, mammalian target of rapamycin; JAK, janus kinase; STAT, signal transducer and activator of transcription.
Mentions: The HER receptors are composed of a large extra-cellular ligand-binding domain, which has four subdomains (I–IV), followed by a transmembrane domain, a small intracellular juxtamembrane domain preceding the kinase domain, and a C-terminal tail, on which the docking sites for phosphotyrosine-binding effector molecules are found (10). These four receptors form homo-dimers and hetero-dimers, which are associated with instigation of different downstream pathways. Emerging targeted treatment has focused on inhibition of these HER receptors via either external monoclonal antibodies (mAb) or small molecule tyrosine kinase inhibitors (TKIs). Figure 1 presents a simplified summary of the HER signaling pathways.

Bottom Line: Hyper-activation of the HER (erbB) family receptors, HER 1-4, leads to up-regulation of the three vital signaling pathways: mitogen activated protein kinase, phosphoinositide 3-kinase/AKT, and Janus kinase/signal transducer and activator of transcription pathways.The emergence of an anti-panHER approach to blockade of these pathways as a cancer treatment may provide a solution to this resistance.Recent literature associated with HER signaling pathways and panHER inhibition was reviewed through PubMed and Medline database, followed by critical comparison and analysis.

View Article: PubMed Central - PubMed

Affiliation: Sarcoma Nano-Oncology Group, Adult Cancer Program, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales (UNSW) , Sydney, NSW , Australia ; Department of Surgery, Prince of Wales Clinical School, University of New South Wales (UNSW) , Sydney, NSW , Australia.

ABSTRACT

Purpose: Hyper-activation of the HER (erbB) family receptors, HER 1-4, leads to up-regulation of the three vital signaling pathways: mitogen activated protein kinase, phosphoinositide 3-kinase/AKT, and Janus kinase/signal transducer and activator of transcription pathways. Blocking HER1/EGFR has a limited anticancer effect due to either secondary mutation e.g., T790M or by-pass signaling of other HER members. The emergence of an anti-panHER approach to blockade of these pathways as a cancer treatment may provide a solution to this resistance. This review aimed to provide an overview of the HER signaling pathways and their involvement in tumor progression and examine the current progress in panHER inhibition.

Methods: Recent literature associated with HER signaling pathways and panHER inhibition was reviewed through PubMed and Medline database, followed by critical comparison and analysis.

Results: Pre-clinical studies and clinical trials of panHER inhibitors show promising results, and the potential to improve patient outcomes in solid cancers.

Conclusion:  The use of panHER inhibitors in cancers with HER-family hyper-activation, such as other epithelial cancers and sarcoma, is a new direction to research and has potential in clinical cancer therapy in the future.

No MeSH data available.


Related in: MedlinePlus