Loss of homotypic cell adhesion by epithelial-mesenchymal transition or mutation limits sensitivity to epidermal growth factor receptor inhibition.
Overexpression and enhanced activation of the epidermal growth factor receptor (EGFR) is frequently observed in human carcinomas. Inhibitors of EGFR signaling have shown clinical utility; however, understanding response at the molecular level is important to define patient subsets most likely to benefit, as well as to support the rational design of drug combinations. Pancreatic and colorectal tumor cell lines insensitive to EGFR inhibition were those that had lost or mutated the epithelial junction constituents E-cadherin and gamma-catenin, had lost homotypic adhesion, and often gained proteins associated with an epithelial to mesenchymal-like transition, such as vimentin, zeb1, or snail. In matched pairs of colorectal tumor cells, the epithelial lines showed an average 7-fold greater sensitivity than mesenchymal-like lines. In human pancreatic and colorectal tumor tissues, gain of mesenchymal characteristics and loss of epithelial characteristics correlated with advancing tumor stage. These data indicate an especially sensitive patient subset as well as a rationale for the combination of EGFR antagonists with agents that affect the epithelial to mesenchymal-like transition process as a mechanism to enhance sensitivity for more advanced mesenchymal-like tumors.
Buck
Elizabeth
E
OSI Pharmaceuticals, Inc., 1 Bioscience Park Drive, Farmingdale, NY 11735, USA.
Eyzaguirre
Alexandra
A
Barr
Sharon
S
Thompson
Stuart
S
Sennello
Regina
R
Young
David
D
Iwata
Kenneth K
KK
Gibson
Neil W
NW
Cagnoni
Pablo
P
Haley
John D
JD
D014408:Biomarkers, Tumor / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D004847:Epithelial Cells / Q000473:pathology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D006801:Humans; D007124:Immunoenzyme Techniques; D008648:Mesoderm / Q000473:pathology*; D009154:Mutation / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D046888:Tissue Array Analysis; D014746:Vimentin / Q000378:metabolism
D014408:Biomarkers, Tumor; D015820:Cadherins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D014746:Vimentin; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors