Resistance to ErbB2 tyrosine kinase inhibitors in breast cancer is mediated by calcium-dependent activation of RelA.
HER2/neu gene amplification and protein overexpression occurs in approximately 15-20% of invasive breast cancers and is associated with poor disease-free survival and resistance to certain chemotherapeutic agents. HER2 overexpression results in activation of multiple intracellular signalling pathways, including the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) cascades which act to modulate cellular proliferative and survival responses, and tumours overexpressing HER2 have been found to be more aggressive in comparison with tumours that do not. In addition, many HER2-positive tumours also display autocrine epidermal growth factor receptor (EGFR) activation, and interaction between HER2 and the EGFR may contribute to the increased rates of proliferation. Also, although HER2-inhibtors such as trastuzumab have proven effectiveness in HER2-positive cancers, cross-talk between the other extracellular HER-family proteins (e.g. HER2 and the EGFR) may provide the cell with a potential bypass mechanism for resistance.
These observations have provided a strong rationale for inhibition of both EGFR and HER2 in the treatment of HER2-positive tumours and have led to the development of lapatinib, which is a small-molecule, dual tyrosine-kinase inhibitor of EGFR and HER2 currently approved for use in HER2-positive breast cancer. However, despite the clinical success of such agents, their long-term efficacy is limited by the development of therapeutic resistance.
In their recent study, Xia and colleagues have investigated the potential mechanisms that underlie lapatinib resistance in breast cancer. They report that RelA, a member of the nuclear factor-kappaB (NF-[kappa]B) transcriptional factor family, was found to be activated by lapatinib in both HER2-positive breast cancer cell lines and in HER2-positive breast cancer patients. Subsequently, genetic inhibition of RelA expression led to increased apoptosis in response to lapatinib in both lapatinib-sensitive and lapatinib-resistant breast cancer cells. To establish the clinical relevance of their in vitro findings, the authors investigated RelA activation in pre- and post-lapatinib treatment biopsies from HER2-positive cancers. These data revealed that increased phospho-RelA expression in tumours treated with lapatinib monotherapy correlated with a poorer clinical outcome.
Breast cancer continues to adapt to the treatments available, and clinicians must alter treatment regimens to overcome the disease. Elucidating the adaptive mechanisms that contribute to therapeutic resistance is an important step in development of newer, more effective therapies. The findings of Xia et al. suggest that RelA may present a potential therapeutic target to enhance the clinical efficacy of lapatinib in HER2-positive breast cancers.
Correspondence to: Stephen Hiscox
Welsh School of Pharmacy
Redwood Building, Cardiff University
Cardiff CF10 3NB, Wales, UK
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|Publication:||Advances in Breast Cancer|
|Date:||Apr 1, 2010|
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