The widespread clinical use of
therapies targeting the ErbB2
receptor tyrosine kinase oncogene represents a significant advance in
breast cancer treatment. However, the development of therapeutic resistance represents a dilemma limiting their clinical efficacy, particularly small-molecule
tyrosine kinase inhibitors that block ErbB2 autophosphorylation and activation. Here, we show that
lapatinib (
GW572016), a highly selective, small-molecule inhibitor of the ErbB2 and
epidermal growth factor receptor tyrosine kinases, which was recently approved for the treatment of advanced-stage ErbB2(+)
breast cancer, unexpectedly triggered a cytoprotective stress response in ErbB2(+)
breast cancer cell lines, which was mediated by the
calcium-dependent activation of RelA, the prosurvival subunit of
NF-kappaB. Abrogation of
lapatinib-induced RelA activation using either
small interfering RNA constructs or an intracellular
calcium chelator enhanced the apoptotic effects of
lapatinib in parental ErbB2(+)
breast cancer cells and overcame therapeutic resistance to
lapatinib in ErbB2(+)
breast cancer lines that had been rendered resistant to
lapatinib through chronic exposure to the
drug, mimicking the clinical setting. In addition, analysis of changes in phospho-RelA expression in sequential clinical biopsies from ErbB2(+) breast
cancers treated with
lapatinib monotherapy revealed marginally statistically significant differences between responders and nonresponders, which was consistent with our preclinical findings. Elucidating the regulation of RelA by
lapatinib in ErbB2(+) breast
cancers, and showing its role in the development of therapeutic resistance to
lapatinib, identifies another therapeutic target to overcome or prevent the onset of resistance to
lapatinib in some women with ErbB2(+) breast
cancers.