Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer that does not currently have any targeted therapeutics available. TNBC is characterized by the lack of expression of human epidermal growth factor receptor 2 (HER2 or EGFR2), estrogen receptor, and progesterone receptor, which are expressed in other types of breast cancers and can be targeted directly in those cases. TNBC cell growth is likely not fueled by estrogen, progesterone, or Her2 (the ligands for the three absent receptors), and therefore hormonal therapy or anti-Her2 treatments are likely to be ineffective.
Current TNBC drug treatments consist primarily of standard systemic chemotherapies. TNBC patients respond differently to the various current treatments, and this indicates that the drivers of cancer for TNBC patients may differ between patients. TNBC cells from some patients appear to lack the ability to repair DNA damage efficiently, so platinum-containing drugs that cause DNA damage are being investigated in several clinical trials.
About 50% of TNBC cells express epidermal growth factor receptor (EGFR), and indeed clinical trials have been undertaken to target EGFR with antibodies or tyrosine kinase inhibitors or with combinations of an anti-EGFR antibody and a standard chemotherapeutic agent. There are currently many ongoing trials, which predominantly focus on combinations of agents to treat TNBC. The authors* here have investigated antibodies against EGFR that can be used concurrently and lead to synergy. They were able to find two EGFR antibodies (panitumumab and mAb111) that are noncompetitive for binding to EGFR (i.e., binding of one does not preclude binding of the other).
The combination increased EGFR ubiquitination, which is often associated with receptor degradation (Figure 1). Additionally, pretreatment with bortezomib or bafilomycin before treatment of the antibody pair was used to try to tease out mechanism. Degradation was inhibited by the inhibitor of lysosomal hydrolases (bafilomycin) but not by an inhibitor of the proteasome degradation system (bortezomib; see Figure 1, panel C).
The effect of single agents versus combinations was also studied (Figure 2). EGFR was degraded by combinations of antibodies but not by the single agents. Additionally, a 50% reduction in cell migration (via an invasion assay) was observed in combination but not with single agents.