THE GROWTH-RESPONSE OF HUMAN TUMOR-CELL LINES EXPRESSING THE EGF RECEPTOR TO TREATMENT WITH EGF AND OR MABS THAT BLOCK LIGAND-BINDING

We have investigated the effect of treatment with epidermal growth fac tor (EGF) and/or monoclonal antibodies (Mabs) to the epidermal growth factor receptor (EGFR) on the growth in vitro of a number of human tum our cell lines. Mabs ICR10, ICR11, and ICR16 that prevent the binding of both I-125-EGF and I-125-TGFalpha to the EGF receptor were found to inhibit the growth of human tumour cell lines overexpressing the EGF receptor. At high concentrations (5 nM), EGF was also found. to inhibi t the growth of HN5, A431 and MDA MB-468 cells whereas the proliferati on of SKBR3 and HN6 cells was stimulated. While some of the cell lines (e.g. HN5 and HN6) were very susceptible to growth inhibition by anti bodies to the EGFR others, known to secrete autocrine growth factors ( e.g. A431 and MDA MB-468), were less affected by these antibodies. Ind eed, growth of the latter cell lines was inhibited more effectively by the addition of 5 nM of exogenous EGF than by treatment with 156 nM o f the anti-EGFR Mabs ICR16, ICR11, and ICR10. In addition, we show tha t the growth of HN5 cells, which express very large numbers of EGF rec eptors (1.4x10(7)/cell), was stimulated at picomolar concentrations of EGF but inhibited at concentrations of EGF in the nanomolar range. Ma ximal stimulation (25% above control) was observed with the addition o f 78 pM EGF to the cultures. The mitogenic effect of low concentration s of EGF and the growth inhibitory effect of nanomolar concentrations of EGF on HN5 cells could be reversed by the addition of 156 nM of the anti-EGFR antibodies. We conclude that growth inhibition can follow f rom either inhibition of signal transduction by blocking ligand bindin g to the EGFR or from excess binding of ligand. With tumours that prod uce significant quantities of autocrine growth factors the latter will compete with the Mabs for binding to the receptor and reduce their ef fectiveness.