The human epidermal growth factor receptor 2 (HER2) is a transmembrane receptor with tyrosine kinase activity overexpressed in about 20% to 25% of invasive carcinomas of the breast. Patients with such tumors have different responses to therapeutic agents and a worse outlook, with reduced progression-free and overall survival, compared with patients harboring HER2-negative tumors. Trastuzumab (Herceptin) is a humanized IgG1 monoclonal antibody against the extracellular domain of HER2. The combined use of trastuzumab and chemotherapy in randomized trials has resulted in an increase in overall survival rates in the metastatic setting. Furthermore, adjuvant trastuzumab has been shown to reduce the risk of recurrence or death in early-stage breast cancer.
Even though such results have been achieved in patients selected for the presence of HER2 overexpression or gene amplification, a sizable fraction of patients do not respond to initial therapy with trastuzumab, either as a single agent or in combination with chemotherapy, and the vast majority of patients initially responding develop resistance to treatment within 1 year. Such findings suggest that both de novo and acquired mechanisms of therapeutic resistance are important causes of treatment failure.
Because of the complex and redundant signaling pathways of the ErbB family of receptors, which have more than 30 different extracellular domains and more than 50 intracellular effectors, the mechanisms potentially involved in trastuzumab resistance are multiple. In addition, the activation of other receptor families and the abnormal function of their respective signaling pathways, as well as the abnormal activity of several other intracellular molecules that behave as messengers or moderators of these signaling cascades, might also play a role in determining resistance to trastuzumab.
This review will discuss several molecular mechanisms that can lead to the development of trastuzumab resistance, as well as the possibility of exploring these aberrations as therapeutic targets that could help avoid or overcome resistance to trastuzumab, thus enhancing the therapeutic arsenal and the life expectancy of patients with HER2-positive breast cancer.
Postulated Mechanisms of Action of Trastuzumab
Despite the absence of a known direct ligand, the catalytic activity of HER2 is a result of its homo- and heterodimerization with other receptors of the ErbB family, such as the epidermal growth factor receptor (EGFR), HER3, and HER4. Through its binding with high affinity to HER2, trastuzumab is able to block intracellular signaling via the mitogen-activated protein kinase (MAPK) and the phosphatidylinositol 3-kinase (PI3K) pathways.[5,6] The MAPK pathway is critical for tumor cell proliferation, and the PI3K pathway leads to phosphorylation and activation of AKT, with inhibition of apoptosis.
Blocking these pathways leads to the accumulation of the p27Kip1, an inhibitor of cyclin-dependent kinases, thus inhibiting the cyclin E/Cdk2 complex and leading to cell-cycle arrest in G1/S and induction of apoptosis. Trastuzumab therapy also increases membrane localization and activity of PTEN, the protein product of the phosphatase and tensin homolog deleted on chromosome 10 gene, by reducing PTEN tyrosine phosphorylation via Src tyrosine kinase inhibition. Increased PTEN activity thus inhibits the PI3K pathway and cell proliferation.
Immune response activation through antibody-dependent cellular cytotoxicity is another potential mechanism of action of trastuzumab. Natural killer (NK) cells that express the Fc-gamma receptor are able to bind to trastuzumab and induce cell lysis. Trastuzumab was able to inhibit the outgrowth of macroscopically detectable xenograft tumors for up to 7 weeks in mice inoculated with positive and intrinsically trastuzumab-resistant HER2 cells. This effect is likely to be mediated via antibody-dependent cellular cytotoxicity, since the same phenomenon did not occur when trastuzumab-F(ab′) was used.
Gennari et al evaluated 11 patients with HER2-positive breast cancer treated in the neoadjuvant setting with trastuzumab. Surgical samples, tumor biopsies, and lymphocytes from these patients were collected for biologic studies. Patients with complete or partial remissions were found to have a higher in situ infiltration of leukocytes and a higher capability to mediate in vitro antibody-dependent cellular cytotoxicity activity.
Trastuzumab might also play a role as an antiangiogenic agent, since it has been shown to induce normalization and regression of the vasculature in a murine experimental human breast tumor model that overexpresses HER2. The combined use of trastuzumab plus paclitaxel more effectively inhibited HER2-mediated angiogenesis than either treatment alone, resulting in more pronounced tumoricidal effects.
When overexpressed, the HER2 receptor is subjected to proteolysis, with the consequent cleavage and release to the circulation of the extracellular portion (p95HER2). The HER2 extracellular domain represents a truncated form of the HER2 receptor possessing intrinsic kinase activity in vitro. In patients with breast cancer, the presence of soluble extracellular domain appears to help distinguish tumors that have metastasized to the lymph nodes from those with negative nodes. In addition, elevated levels of circulating HER2 extracellular domain in patients with metastatic breast cancer correlate with reduced efficacy of a paclitaxel/doxorubicin chemotherapy combination. Trastuzumab treatment inhibits the proteolytic cleavage of HER2 and prevents the production of the active truncated HER2 fragment, which may constitute another mechanism of action of trastuzumab.
Postulated Mechanisms of Resistance to Trastuzumab
Loss of PTEN
Patients with PTEN-deficient breast cancer had significantly poorer responses to trastuzumab-based therapy than those with normal PTEN.[8,15] Thus, PTEN deficiency might be a useful predictor of clinical resistance to trastuzumab.
Nagata et al have demonstrated that reducing PTEN in breast cancer cell lines by using antisense oligonucleotides conferred trastuzumab resistance in vitro and in vivo. This process seems to be secondary to the reduction in AKT phosphorylation. Treatment of these tumor cells with inhibitors of the PI3K pathway was capable of overcoming resistance to trastuzumab. In that study, the analysis of 47 patients with metastatic breast cancer treated with trastuzumab plus a taxane showed that loss of PTEN expression was associated with lower response.
Fujita et al have found a remarkable activity for trastuzumab in patients whose tumors had elevated PTEN expression on immunohistochemistry. Moreover, they found that duplex siRNA targeting PTEN significantly decreased the trastuzumab chemosensitivity of SKBR3 cells.
These results suggest that the loss of PTEN can be used as a predictor of resistance to trastuzumab and that the use of drugs that inhibit PI3K can provide a therapeutic alternative in patients with low PTEN concentration.
Activation of Alternative Pathways
The insulin-like growth factor–I receptor (IGF-IR) is a transmembrane tyrosine kinase receptor associated with cell proliferation and metastasis formation. In breast cancer cell lines that overexpress HER2, an increased level of IGF-IR activation appears to interfere with the effectiveness of trastuzumab. Thus, strategies that target the IGF-IR signaling pathway may prevent or delay development of resistance to trastuzumab.
Nahta et al observed a cross-talk between HER2 and IGF-IR in trastuzumab-resistant, but not in trastuzumab-sensitive, cell lines. The cross-talk between IGF-IR and HER2 in resistant cells is evidenced by the fact that IGF-I stimulation results in increased phosphorylation of HER2 in such cells; conversely, inhibition of IGF-IR tyrosine kinase activity leads to decreased HER2 phosphorylation in such resistant cells.
The cyclin-dependent kinase inhibitor p27Kip1 was found to be decreased in trastuzumab-resistant breast tumor cells, and cyclin-dependent kinase 2 activity was increased. Importantly, the exogenous addition of p27Kip1 increased trastuzumab sensitivity. Additionally, resistant cells displayed heightened sensitivity to the proteasome inhibitor MG132, which induced p27Kip1 expression. Thus, trastuzumab resistance may be associated with decreased p27Kip1 levels and may be susceptible to treatments that induce p27Kip1 expression.
These data suggest that reduction of the activity of p27Kip1 is associated with resistance to trastuzumab, possibly mediated by the heterodimerization of IGF-IR with HER2. Therefore, IGF-IR can be seen as an important potential therapeutic target in patients who are resistant to trastuzumab.
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