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Trastuzumab: updated mechanisms of action and resistance in breast cancer.

Vu T, Claret FX - Front Oncol (2012)

Bottom Line: In addition, in clinical practice, there are currently no conclusive biomarkers for patient response to trastuzumab.Such understanding will provide the guidance critically needed for the design of better combination therapy and will allow the appropriate selection of patients who are responsive to trastuzumab-based strategies.In line with that, our review highlights the well-accepted mechanisms of action and resistance to the therapy and discusses the progress that has been made toward successfully overcoming this resistance.

View Article: PubMed Central - PubMed

Affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center Houston, TX, USA.

ABSTRACT
HER2-positive breast cancer accounts for 20-30% of all breast cancers and has the second-poorest prognosis among breast cancer subtypes. The approval of trastuzumab in 1998 has significantly improved patients' outcomes and paved the way for the beginning of advent of targeted approaches in breast cancer treatment. However, primary or acquired resistance to trastuzumab has been increasingly recognized as a major obstacle in the clinical management of this disease. In addition, in clinical practice, there are currently no conclusive biomarkers for patient response to trastuzumab. Therefore, understanding the molecular mechanism of trastuzumab and the development of resistance to this drug are of interest. Such understanding will provide the guidance critically needed for the design of better combination therapy and will allow the appropriate selection of patients who are responsive to trastuzumab-based strategies. In line with that, our review highlights the well-accepted mechanisms of action and resistance to the therapy and discusses the progress that has been made toward successfully overcoming this resistance.

No MeSH data available.


Related in: MedlinePlus

HER2 signaling pathway. Receptor homodimerization or heterodimerization is the prerequisite step for HER2 activation. Its activation then triggers a broad spectrum of downstream cascades to promote numerous effects, including cell growth, proliferation, and survival. PI3K/Akt is one of the most well studied pathways activated by HER2. Activated PI3K/Akt also triggers mTOR, a master positive regulator of cell metabolism. In addition, HER2 activation can activate Ras/Raf and MEK pathways, which favors cancer cells’ growth and migration.
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Figure 1: HER2 signaling pathway. Receptor homodimerization or heterodimerization is the prerequisite step for HER2 activation. Its activation then triggers a broad spectrum of downstream cascades to promote numerous effects, including cell growth, proliferation, and survival. PI3K/Akt is one of the most well studied pathways activated by HER2. Activated PI3K/Akt also triggers mTOR, a master positive regulator of cell metabolism. In addition, HER2 activation can activate Ras/Raf and MEK pathways, which favors cancer cells’ growth and migration.

Mentions: HER2 is activated by the formation of homodimers or heterodimers with other EGFR proteins. This dimerization results in autophosphorylation and/or transphosphorylation of specific tyrosine residues in EGFR intracellular domains, which in turn leads to the activation of the Ras/Raf/mitogen-activated protein kinase, the phosphoinositide 3-kinase/Akt, and the phospholipase Cγ (PLCγ)/protein kinase C (PKC) pathways (Browne et al., 2009). Of note, the HER2-HER3 heterodimer is the most potent stimulator of downstream pathways, particularly the PI3K/Akt, a master regulator of cell growth and survival (Alimandi et al., 1995; Lee-Hoeflich et al., 2008). Moreover, HER2 dimerization promotes the mislocalization and rapid degradation of cell cycle inhibitor p27Kip1 protein leading to cell cycle progression. Some of the well studied pathways affected by activation of HER2 are briefly described in Figure 1.


Trastuzumab: updated mechanisms of action and resistance in breast cancer.

Vu T, Claret FX - Front Oncol (2012)

HER2 signaling pathway. Receptor homodimerization or heterodimerization is the prerequisite step for HER2 activation. Its activation then triggers a broad spectrum of downstream cascades to promote numerous effects, including cell growth, proliferation, and survival. PI3K/Akt is one of the most well studied pathways activated by HER2. Activated PI3K/Akt also triggers mTOR, a master positive regulator of cell metabolism. In addition, HER2 activation can activate Ras/Raf and MEK pathways, which favors cancer cells’ growth and migration.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3376449&req=5

Figure 1: HER2 signaling pathway. Receptor homodimerization or heterodimerization is the prerequisite step for HER2 activation. Its activation then triggers a broad spectrum of downstream cascades to promote numerous effects, including cell growth, proliferation, and survival. PI3K/Akt is one of the most well studied pathways activated by HER2. Activated PI3K/Akt also triggers mTOR, a master positive regulator of cell metabolism. In addition, HER2 activation can activate Ras/Raf and MEK pathways, which favors cancer cells’ growth and migration.
Mentions: HER2 is activated by the formation of homodimers or heterodimers with other EGFR proteins. This dimerization results in autophosphorylation and/or transphosphorylation of specific tyrosine residues in EGFR intracellular domains, which in turn leads to the activation of the Ras/Raf/mitogen-activated protein kinase, the phosphoinositide 3-kinase/Akt, and the phospholipase Cγ (PLCγ)/protein kinase C (PKC) pathways (Browne et al., 2009). Of note, the HER2-HER3 heterodimer is the most potent stimulator of downstream pathways, particularly the PI3K/Akt, a master regulator of cell growth and survival (Alimandi et al., 1995; Lee-Hoeflich et al., 2008). Moreover, HER2 dimerization promotes the mislocalization and rapid degradation of cell cycle inhibitor p27Kip1 protein leading to cell cycle progression. Some of the well studied pathways affected by activation of HER2 are briefly described in Figure 1.

Bottom Line: In addition, in clinical practice, there are currently no conclusive biomarkers for patient response to trastuzumab.Such understanding will provide the guidance critically needed for the design of better combination therapy and will allow the appropriate selection of patients who are responsive to trastuzumab-based strategies.In line with that, our review highlights the well-accepted mechanisms of action and resistance to the therapy and discusses the progress that has been made toward successfully overcoming this resistance.

View Article: PubMed Central - PubMed

Affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center Houston, TX, USA.

ABSTRACT
HER2-positive breast cancer accounts for 20-30% of all breast cancers and has the second-poorest prognosis among breast cancer subtypes. The approval of trastuzumab in 1998 has significantly improved patients' outcomes and paved the way for the beginning of advent of targeted approaches in breast cancer treatment. However, primary or acquired resistance to trastuzumab has been increasingly recognized as a major obstacle in the clinical management of this disease. In addition, in clinical practice, there are currently no conclusive biomarkers for patient response to trastuzumab. Therefore, understanding the molecular mechanism of trastuzumab and the development of resistance to this drug are of interest. Such understanding will provide the guidance critically needed for the design of better combination therapy and will allow the appropriate selection of patients who are responsive to trastuzumab-based strategies. In line with that, our review highlights the well-accepted mechanisms of action and resistance to the therapy and discusses the progress that has been made toward successfully overcoming this resistance.

No MeSH data available.


Related in: MedlinePlus