EXPRESSION OF A TRUNCATED EGF RECEPTOR IS ASSOCIATED WITH INHIBITION OF PANCREATIC-CANCER CELL-GROWTH AND ENHANCED SENSITIVITY TO CISPLATINUM

Human pancreatic cancers over-express the epidermal growth factor rece ptor (EGF-R) and all 5 known ligands of the EGF family, including EGF, transforming growth factor-alpha (TGF-alpha), amphiregulin, betacellu lin and heparin-binding EGF-like growth factor (HB-EGF). The aim of th e present study was to confirm the presence of EGF-R-dependent autocri ne loops in a human pancreatic cancer cell line and to explore the pos sibility that interrupting EGF-R activation by introducing a truncated receptor abrogates pancreatic cancer cell growth. The anchorage-indep endent growth of PANC-I human pancreatic cancer cells, previously show n to express TGF-alpha, was inhibited by specific anti TGF-alpha antib odies, PANC-I cells were then either transfected with an expression pl asmid encoding a kinase-deficient EGF-R cDNA (HER653) or infected with the same EGF-R cDNA using a retroviral vector. Multiple transfected a nd infected crones co-expressed the truncated EGF-R and endogenous EGF -R as revealed by Northern blot analysis and immunoblots. In these clo nes, there was a marked attenuation in EGF- and TGF-alpha-mediated EGF -R tyrosine phospharylation and c-fos induction. There was also a sign ificant decrease in colony formation in soft agar by comparison with c ontrol cells and a significant increase in the effect of the growth-in hibitory effect of the alkylating agent cisplatinum in these clones. O ur observations indicate that dominant negative inhibition of EGF-R ma y have therapeutic potential in pancreatic cancer. (C) 1996 Wiley-Liss , Inc.