Activated epidermal growth factor receptor as a novel target in pancreatic cancer therapy.
Pancreatic cancer is one of the most fatal among all solid malignancies. Targeted therapeutic approaches have the potential to transform cancer therapy as exemplified by the success of several tyrosine kinase inhibitors. Prompted by this, comprehensive profiling of tyrosine kinases and their substrates was carried out using a panel of low passage pancreatic cancer cell lines. One of the pancreatic cancer cell lines, P196, which showed dramatic upregulation of tyrosine kinase activity as compared to non-neoplastic cells, was systematically studied using a quantitative proteomic approach called stable isotope labeling with amino acids in cell culture (SILAC). A careful analysis of activated tyrosine kinase pathways revealed aberrant activation of epidermal growth factor receptor pathway in this cell line. Mouse xenograft based studies using EGFR inhibitor erlotinib confirmed EGFR pathway to be responsible for proliferation in these tumors. By a systematic study across low passage pancreatic cancer cell lines and mice carrying pancreatic cancer xenografts, we have demonstrated activated epidermal growth factor receptor as an attractive candidate for targeted therapy in a subset of pancreatic cancers. Further, we propose immunohistochemical labeling of activated EGFR (pEGFR (1068)) as an efficient screening tool to select patients who are more likely to respond to EGFR inhibitors.
Harsha
H C
HC
Institute of Bioinformatics, International Technology Park, Bangalore 560 066, India.
Jimeno
Antonio
A
Molina
Henrik
H
Mihalas
Anca B
AB
Goggins
Michael G
MG
Hruban
Ralph H
RH
Schulick
Richard D
RD
Kamath
Ullas
U
Maitra
Anirban
A
Hidalgo
Manuel
M
Pandey
Akhilesh
A
D000818:Animals; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D005260:Female; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics / Q000379:methods; D011799:Quinazolines / Q000494:pharmacology*; D013379:Substrate Specificity; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases