HER2-amplified breast cancer: mechanisms of trastuzumab resistance and novel targeted therapies - PubMed (original) (raw)

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HER2-amplified breast cancer: mechanisms of trastuzumab resistance and novel targeted therapies

Devika Gajria et al. Expert Rev Anticancer Ther. 2011 Feb.

Abstract

HER2 amplification is seen in up to 20% of breast cancers and is associated with an aggressive phenotype. Trastuzumab, a monoclonal antibody to HER2, accrues significant clinical benefit in the metastatic and adjuvant settings. However, some patients suffer disease recurrence despite adjuvant trastuzumab therapy, and many patients with metastatic disease do not respond to therapy or develop refractory disease within 1 year of treatment. Given the increased recognition of de novo and acquired resistance to therapy, considerable research has been dedicated to understanding the molecular mechanisms of trastuzumab resistance. Here, we highlight putative models of resistance, including activation of the downstream PI3K-signaling pathway, accumulation of a constitutively active form of HER2, and crosstalk of HER2 with other growth factor receptors. The identification of these specific mechanisms of trastuzumab resistance has provided a rationale for the development of several novel HER2-targeted agents as the mechanisms have largely suggested a continued tumor dependence on HER2 signaling. We explore the emerging data for the treatment of trastuzumab-refractory disease with novel agents including lapatinib, neratinib, pertuzumab, trastuzumab-DM1, HSP90 and PI3K pathway inhibitors, and the future potential for these inhibitors which, if combined with reliable biomarkers of resistance, may ultimately usher in a new era of personalized medicine for this disease.

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Figures

Figure 1

Figure 1. Proposed mechanisms of resistance to trastuzumab

(A) HER2 signal transduction. Activation of the receptor tyrosine kinase occurs by homodimerization or heterodimerization with other HER family members. Activated HER2 initiates downstream signaling through the PI3K–AKT–mTOR pathway, promoting cell proliferation and survival. (B) Downstream activation of the PI3K pathway. PI3K is composed of an 85-kD regulatory subunit and a 110-kD catalytic subunit (PIK3CA), and upon subunit catalyzes phosphorylation of phosphatidylinositol bisphosphate at the membrane (PIP2) to phosphatidylinositol triphosphate promotes membrane localization and activation of downstream effector proteins such as AKT that stimulate cell proliferation. (PIP3). PIP3 or loss of PTEN result PTEN is a negative regulator of PI3K signaling that dephosphorylates PIP3 into PIP2. Activating mutations in PIK3CA in constitutive activation of the PI3K pathway and clinical resistance to trastuzumab therapy. (C) Accumulation of p95-HER2. The constitutively active truncated form of HER2, p95-HER2, lacks the trastuzumab-binding site. The intracellular kinase downstream signaling in the presence of trastuzumab, leading to increased cell proliferation. (D) Increased signaling from alternative receptors. Overexpression or activation of other receptors may drive growth factor signaling, either through trastuzumab-insensitive dimers with HER2 or in a HER2-independent fashion.

Figure 2

Figure 2. Sites of action of novel agents for HER2-amplified breast cancer

(A) Lapatinib is a dual EGF receptor (EGFR)/HER2 tyrosine kinase inhibitor approved for use in trastuzumab-refractory patients. Neratinib is an irreversible tyrosine kinase inhibitor of EGFR/HER2. (B) Pertuzumab, a monoclonal antibody to HER2, binds to HER2 at a distinct epitope from where trastuzumab binds and prevents ligand-induced heterodimerization with HER3. Dysregulated activation of the PI3K–AKT–mTOR pathway can mediate trastuzumab resistance, and molecular therapies aimed at directly inhibiting PI3K, AKT and mTOR are therefore in development. (C) HSP90 inhibitors promote HER2 degradation by blocking the activity of HSP90, a chaperone protein that protects HER2 from proteasomal degradation. (D) TDM-1, the antibody–drug conjugate of trastuzumab and maytansine, allows for delivery of a potent microtubule inhibitor selectively into HER2-overexpressing cells.

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