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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

Resistant mechanism to trastuzumab. (1) Steric effects or masking of the trastuzumab-binding sites. The truncated form of HER2 (p95HER2) that lacks trastuzumab-binding domain can no longer be inhibited by trastuzumab. The remaining structure can still dimerize with other receptors and therefore can still trigger downstream cascades. (2) Alternative elevations of other receptor tyrosine kinases. The overexpression of other growth factor receptors, such as c-Met and IGF-1R, the two most commonly reported, can trigger similar effects on cell behavior, even though HER2 signaling is inhibited by trastuzumab. (3) Intracellular alterations. In trastuzumab resistant cells, PTEN function is lost; thus, Akt is constitutively active. Also, resistant cells can harbor activating mutations in PI3K or Akt, which can trigger other downstream signaling pathways even when HER2 is blocked by trastuzumab or when PTEN is active.
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Figure 2: Resistant mechanism to trastuzumab. (1) Steric effects or masking of the trastuzumab-binding sites. The truncated form of HER2 (p95HER2) that lacks trastuzumab-binding domain can no longer be inhibited by trastuzumab. The remaining structure can still dimerize with other receptors and therefore can still trigger downstream cascades. (2) Alternative elevations of other receptor tyrosine kinases. The overexpression of other growth factor receptors, such as c-Met and IGF-1R, the two most commonly reported, can trigger similar effects on cell behavior, even though HER2 signaling is inhibited by trastuzumab. (3) Intracellular alterations. In trastuzumab resistant cells, PTEN function is lost; thus, Akt is constitutively active. Also, resistant cells can harbor activating mutations in PI3K or Akt, which can trigger other downstream signaling pathways even when HER2 is blocked by trastuzumab or when PTEN is active.

Mentions: Even though trastuzumab has significantly improved outcome in breast cancer patients and has paved the way for the era of targeted therapy in breast cancer treatment, the median duration of response is modest (Gajria and Chandarlapaty, 2011; Zhang et al., 2011). This is due to either primary or secondary mechanisms of resistance to the therapy. Less than 35% of patients with HER2-positive breast cancer initially respond to trastuzumab (Wolff et al., 2007; Narayan et al., 2009), which means these patients are “primarily” or “inherently” resistant to the drug. On the other hand, about 70% of patients who initially responded experience progression to metastatic disease within a year (Gajria and Chandarlapaty, 2011), suggesting that “secondary” or “acquired” resistance to trastuzumab frequently develops. Some tumor suppressor proteins and oncoproteins, such as PTEN and Src, have biological significance and play overlapping roles in both primary and acquired resistance (Nagata et al., 2004; Zhang et al., 2011). On the other hand, little information on the basis of primary and secondary resistance is available (Narayan et al., 2009). In this review, we classified the potential mechanisms of resistance to trastuzumab according to the inter- or intra-networks of HER2 signaling. These are summarized in three major categories, briefly described in Figure 2: (1) the steric effects, such as the structural mutation in HER2 protein, (2) the alternative elevations of other tyrosine kinase receptors, such as insulin-like growth factor receptor (IGFR), or (3) the intracellular alterations in HER2 downstream signaling, notably phosphatase and tensin homolog (PTEN) deficiency and/or PI3K/Akt constitutive active.


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

Vu T, Claret FX - Front Oncol (2012)

Resistant mechanism to trastuzumab. (1) Steric effects or masking of the trastuzumab-binding sites. The truncated form of HER2 (p95HER2) that lacks trastuzumab-binding domain can no longer be inhibited by trastuzumab. The remaining structure can still dimerize with other receptors and therefore can still trigger downstream cascades. (2) Alternative elevations of other receptor tyrosine kinases. The overexpression of other growth factor receptors, such as c-Met and IGF-1R, the two most commonly reported, can trigger similar effects on cell behavior, even though HER2 signaling is inhibited by trastuzumab. (3) Intracellular alterations. In trastuzumab resistant cells, PTEN function is lost; thus, Akt is constitutively active. Also, resistant cells can harbor activating mutations in PI3K or Akt, which can trigger other downstream signaling pathways even when HER2 is blocked by trastuzumab or when PTEN is active.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Resistant mechanism to trastuzumab. (1) Steric effects or masking of the trastuzumab-binding sites. The truncated form of HER2 (p95HER2) that lacks trastuzumab-binding domain can no longer be inhibited by trastuzumab. The remaining structure can still dimerize with other receptors and therefore can still trigger downstream cascades. (2) Alternative elevations of other receptor tyrosine kinases. The overexpression of other growth factor receptors, such as c-Met and IGF-1R, the two most commonly reported, can trigger similar effects on cell behavior, even though HER2 signaling is inhibited by trastuzumab. (3) Intracellular alterations. In trastuzumab resistant cells, PTEN function is lost; thus, Akt is constitutively active. Also, resistant cells can harbor activating mutations in PI3K or Akt, which can trigger other downstream signaling pathways even when HER2 is blocked by trastuzumab or when PTEN is active.
Mentions: Even though trastuzumab has significantly improved outcome in breast cancer patients and has paved the way for the era of targeted therapy in breast cancer treatment, the median duration of response is modest (Gajria and Chandarlapaty, 2011; Zhang et al., 2011). This is due to either primary or secondary mechanisms of resistance to the therapy. Less than 35% of patients with HER2-positive breast cancer initially respond to trastuzumab (Wolff et al., 2007; Narayan et al., 2009), which means these patients are “primarily” or “inherently” resistant to the drug. On the other hand, about 70% of patients who initially responded experience progression to metastatic disease within a year (Gajria and Chandarlapaty, 2011), suggesting that “secondary” or “acquired” resistance to trastuzumab frequently develops. Some tumor suppressor proteins and oncoproteins, such as PTEN and Src, have biological significance and play overlapping roles in both primary and acquired resistance (Nagata et al., 2004; Zhang et al., 2011). On the other hand, little information on the basis of primary and secondary resistance is available (Narayan et al., 2009). In this review, we classified the potential mechanisms of resistance to trastuzumab according to the inter- or intra-networks of HER2 signaling. These are summarized in three major categories, briefly described in Figure 2: (1) the steric effects, such as the structural mutation in HER2 protein, (2) the alternative elevations of other tyrosine kinase receptors, such as insulin-like growth factor receptor (IGFR), or (3) the intracellular alterations in HER2 downstream signaling, notably phosphatase and tensin homolog (PTEN) deficiency and/or PI3K/Akt constitutive active.

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