ErbB-dependent signaling as a determinant of trastuzumab resistance.

The pathogenesis of breast cancer is profoundly influenced by the signaling cascades downstream of the human epidermal growth factor receptor (HER; also known as the ErbB receptor) family of receptor tyrosine kinases and by the HER ligands (1, 2). Abnormalities in the expression and activity of HERs and resulting signaling pathways in human breast tumors contribute to the invasion and progression of breast tumors and maintenance of the malignant phenotype. For example, overexpression of the HER2 receptor gene product is frequently associated with an aggressive clinical course, decreased diseasefree survival duration, poor prognosis, and increased metastasis in human breast cancer (3). A large body of work over the past decade has established that the biological outcome of overexpression of HER family members, particularly HER2 and epidermal growth factor receptor (EGFR), is affected not only by the signals originating from the given receptor but also by the trans-heterodimerization of HER family members on stimulation of cancer cells with the HER ligands (1–4). Thus, formation of various combinational HER heterodimers in growth factor–stimulated breast cancer cells is accompanied by differential stimulation of signaling pathways, some of which are overlapping whereas others select to a specific heterodimer or heterodimers. In spite of these developments, the role of HER-triggered signaling pathways as potential determinants of the sensitivity of breast cancer to HER2directed therapies remains poorly understood and is just beginning to unfold. The last decade has been one of the most exciting periods in breast cancer therapy, leading to significant treatment advances in patients with HER2-overexpressing breast cancer with targeting of the ectodomain of HER2 with the anti-HER2 monoclonal antibody trastuzumab (Herceptin; ref. 5). Trastuzumab induces clinical responses in three HER2-positive breast tumors and prolongs the survival of patients with breast cancer when combined with chemotherapy. However, regardless of the presence of HER2 overexpression, a significant proportion of patients with breast cancer do not have a response to trastuzumab-based therapy, and most who do have a response eventually experience resistance to it (6–8). The mechanism of trastuzumab resistance is not fully understood at the moment but is believed to result from the inability of trastuzumab to interfere with the formation of HER2 heterodimers by EGFR or HER3 in HER ligand–stimulated cells (9–11), hyperactivation of phosphatidylinositol 3-kinase caused by either defective phosphatase and tensin homologue (12) or increased levels of insulin-like growth factor 1 receptor (13, 14), and generation of kinase-active COOH-terminal fragments of HER2 (15). Although this research has been very fruitful, a more complete understanding of critical intrinsic signaling cascades in the context of trans -regulation of HERs by their ligands in physiologically relevant models clearly should be combined with examination of human breast tumor specimens for further gains. A deeper understanding of signaling pathways that may still be active in the presence of trastuzumab and further understanding of HER heterodimerization will not only provide a mechanistic explanation for the widely acknowledged clinical phenomenon of trastuzumab resistance of HER2-positive breast tumors but also offer unique opportunities to enhance the sensitivity of antibody-based therapy. In this issue of Clinical Cancer Research , Ritter et al. (16) report an association between active involvement of EGFRinitiated signals and trastuzumab resistance in the absence of detectable defects in the cell-surface expression of HER2 and its binding affinity to radiolabeled trastuzumab in the model cells. Investigators have used a variety of biochemical, cellular, and animal-based assays to draw the conclusion that acquired trastuzumab resistance in the model system is accompanied by a significant increase in the levels of tyrosine-phosphorylated EGFR and EGFR/HER2 dimers at the cell surface because of increased expression of EGFR ligands. The translational novelty of these findings is supported by evidence showing that such trastuzumab-resistant breast cancer cells remain sensitive to designer small-molecule inhibitors of HER tyrosine kinase such as gefitinib, erlotinib, and lapatinib, which are rapidly progressing through preclinical development (17–19). Because trastuzumab-resistant breast cancer cells continue to proliferate even in the presence of trastuzumab, Ritter and colleagues have put forward EGFR ligands and their resulting EGFR stimulation as potential significant mechanisms for sustaining the proliferation of trastuzumab-resistant breast cancer cells, which otherwise remain sensitive to EGFR tyrosine kinase inhibitors. These findings are significant because they offer proof of the notion that the growth of trastuzumabresistant breast cancer cells may be inhibited by targeting of the EGFR pathway by small molecules that target EGFR tyrosine kinase activity. However, at least at the moment, whether similar phenotypic effects can be achieved by treatment with the therapeutic EGFR-blocking antibody C225, the founding member of the concept of receptor tyrosine kinase ectodomain–directed antibody therapy in human cancer (20), Editorial