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Novel strategies for HER-2-positive metastatic disease: mechanisms and therapeutic options to overcome trastuzumab resistance
Breast Cancer Research volume 9, Article number: S23 (2007)
The HER2 tyrosine kinase receptor is overexpressed in approximately 25% of invasive breast cancers, and has been associated with a poor prognosis . Trastuzumab (Herceptin) and lapatinib (Tykerb) are the two therapies currently approved by the FDA for the treatment of HER2-overexpressing metastatic breast cancer. The majority of patients that initially respond to trastuzumab monoclonal antibody-based therapy develop progressive disease within 1 year of treatment initiation . Preclinical studies have indicated several molecular mechanisms that may contribute to the development of trastuzumab resistance . Increased signaling via the phosphatidylinositol 3-kinase/protein kinase B (or Akt) pathway could contribute to trastuzumab resistance due to activation of multiple receptor pathways. These include HER2-related receptors or non-HER receptors such as the insulin-like growth factor-I receptor, which appears to cross-talk to HER2 in resistant cells . Additionally, loss of function of the tumor suppressor PTEN, the negative regulator of Akt, results in heightened Akt signaling that leads to decreased sensitivity to trastuzumab . Decreased interaction between trastuzumab and its target receptor HER2, due to steric hindrance of the HER2 receptor by cell surface proteins, such as MUC-4 , or by the presence of a truncated HER2 protein , may block inhibitory actions of trastuzumab. Novel therapies targeted against these aberrant molecular pathways are being studied in laboratory and clinical settings, and offer hope that the efficacy and duration of response to trastuzumab can be greatly improved.
Lapatinib (Tykerb) is a small molecule tyrosine kinase inhibitor that targets EGFR and HER-2 . Clinical responses were observed in patients with HER2-overexpressing metastatic breast cancer . A recent phase III randomized trial showed that a combination of lapatinib and capecitabine (Xeloda) was superior to capecitabine alone , leading to the FDA approval of lapatinib in 2007. Clinical trials are ongoing to determine the role of lapatinib in the frontline setting for metastatic breast cancer in combination with trastuzumab and taxanes, as well as in the neoadjuvant and adjuvant settings.
Other novel strategies being tested in patients with HER2-over-expressing breast cancer include monoclonal antibodies targeting HER-2 on different epitopes than trastuzumab (for example, pertuzumab), attaching toxins to trastuzumab (for example, trastuzumab-DM1), Hsp90 inhibitors that degrade the HER-2 protein (for example, 17-AAG), irreversible small molecule tyrosine kinase inhibitors (for example, HKI-272), agents directed against IGF-IR and multitarget kinase inhibitors. Indirect approaches include immunotherapy and anti-angiogenic therapy. Clinical trials are evaluating the safety and efficacy of targeted biologic therapies, both as single agents and in combination with other biologics and in combination with standard chemotherapy and endocrine therapy. One of the main challenges is to match the right patient with the right drug(s) at the right time.
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Esteva, F. Novel strategies for HER-2-positive metastatic disease: mechanisms and therapeutic options to overcome trastuzumab resistance. Breast Cancer Res 9, S23 (2007) doi:10.1186/bcr1706