Finding on Tumor Binding Sites May Allow Combo Therapy
Matuzumab, now in clinical trials, may complement cetuximab
Two cancer drugs-one established and one still in clinical trials-bind to receptors on tumor cells in different places at the same time, raising the possibility of designing combination therapy for certain cancers, according to researchers. Cetuximab (Erbitux) is used to treat colorectal and head and neck cancer. Matuzumab is currently in phase two clinical trials for treatment of colorectal, lung, and stomach cancers. Both drugs target epidermal growth factor receptor (EGFR) binding sites on tumor cells.
These findings imply that a combination therapy using both types of EGFR drugs could be developed and tested. This has important implications for the clinical use of matuzumab and for developing new therapies that target EGFR. -Kate Ferguson, PhD, University of Pennsylvania
According to Kate Ferguson, PhD, and colleagues at the University of Pennsylvania (Philadelphia), matuzumab interacts with a site on EGFR that is distinct from the one cetuximab binds to. The binding does not overlap, and both can bind to EGFR at the same time. (Schmiedel J, Blaukat A, Li S, et al. Matuzumab binding to EGFR prevents the conformational rearrangement required for dimerization. Cancer Cell . 2008;13(4):365-373.)
"These findings imply that a combination therapy using both types of EGFR drugs could be developed and tested," Dr. Ferguson says. "This has important implications for the clinical use of matuzumab and for developing new therapies that target EGFR."
In 2005, Dr. Ferguson and colleagues used X-ray crystallography to characterize the interaction between cetuximab and its binding site on EGFR (Li S, Schmitz KR, Jeffrey PD, et al. Structural basis for inhibition of the epidermal growth factor receptor by cetuximab. Cancer Cell . 2005;7(4):301-311). In the current study, the researchers again used X-ray crystallography to examine the binding of matuzumab to its site on EGFR.
"Matuzumab blocks ligand-induced receptor activation indirectly by sterically preventing the domain rearrangement and local conformational changes that must occur for high-affinity ligand binding and receptor dimerization," they concluded.
