AMPHIREGULIN ANTISENSE OLIGONUCLEOTIDE INHIBITS THE GROWTH OF T3M4 HUMAN PANCREATIC-CANCER CELLS AND SENSITIZES THE CELLS TO EGF RECEPTOR-TARGETED THERAPY

Human pancreatic cancers overexpress the epidermal growth factor (EGF) receptor (EGFR) and all 5 ligands that bind to this receptor, includi ng amphiregulin. It is not known, however, whether amphiregulin contri butes in an autocrine manner to enhance pancreatic cancer cell growth, Therefore, we used an amphiregulin antisense oligonucleotide (AR-AS) to suppress amphiregulin expression in T3M4 human pancreatic cancer ce lls, These cells express high levels of EGFR and amphiregulin. AR-AS a bolished amphiregulin immunoreactivity in T3M4 cells, decreased amphir egulin release into the medium and inhibited cell growth in a dose-dep endent manner, Exogenous amphiregulin reversed AR-AS-mediated growth i nhibition, A random oligonucleotide (AR-R) did not alter either cell g rowth or cellular amphiregulin immunoreactivity, AR-AS also increased cellular EGFR protein levels and enhanced the growth inhibitory action s of TP40, a chimeric protein consisting of transforming growth factor -alpha coupled to Pseudomonas exotoxin that internalizes into cells vi a EGFR, These findings indicate that there is an important EGFR/amphir egulin autocrine loop in T3M4 cells and raise the possibility that mod alities aimed at abrogating amphiregulin action may prove useful in pa ncreatic cancer, especially when used in conjunction with EGFR-targete d therapy. (C) 1997 Wiley-Liss, Inc.