Results: 2

Figure 2

Figure 2. Sites of action of novel agents for HER2-amplified breast cancer. From: HER2-amplified breast cancer: mechanisms of trastuzumab resistance and novel targeted therapies.

(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.

Devika Gajria, et al. Expert Rev Anticancer Ther. ;11(2):263-275.
Figure 1

Figure 1. Proposed mechanisms of resistance to trastuzumab. From: HER2-amplified breast cancer: mechanisms of trastuzumab resistance and novel targeted therapies.

(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.

Devika Gajria, et al. Expert Rev Anticancer Ther. ;11(2):263-275.

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