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. 2012 Jun 18:2:62.
doi: 10.3389/fonc.2012.00062. eCollection 2012.

Trastuzumab: updated mechanisms of action and resistance in breast cancer

Thuy Vu  1 , Francois X Claret
Affiliations

Trastuzumab: updated mechanisms of action and resistance in breast cancer

Thuy Vu et al. Front Oncol. .

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.

Keywords: HER2/ERBB2; HER3; breast cancer; herceptin; targeted therapies; trastuzumab.

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Figures

Figure 1
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.
Figure 2
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.
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