EGFR and HER2 inhibition in pancreatic cancer.
The aim of this study was to investigate the effect of lapatinib, a selective inhibitor of EGFR/HER2 tyrosine kinases, on pancreatic cancer cell lines both alone and in combination with chemotherapy. Two cell lines, BxPc-3 and HPAC, displayed the greatest sensitivity to lapatinib (IC(50)<2 μM). Lapatinib also demonstrated some activity in three K-Ras mutated pancreatic cancer cell lines which displayed resistance to erlotinib. Drug effect/combination index (CI) isobologram analysis was used to study the interactions of lapatinib with gemcitabine, cisplatin and 5'deoxy-5'fluorouridine. Concentration-dependent anti-proliferative effects of lapatinib in combination with chemotherapy were observed. To evaluate the potential effect of lapatinib in pancreatic cancer tumours, and to identify a subset of patient most likely to benefit from lapatinib, expression of EGFR and HER2 were investigated in 72 pancreatic cancer tumour specimens by immunohistochemistry. HER2 membrane expression was observed in only 1 % of cases, whereas 44 % of pancreatic tumours expressed EGFR. Based on our in vitro results, lapatinib may provide clinical benefit in EGFR positive pancreatic ductal adenocarcinoma.
Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin, Ireland. naomi.walsh@dcu.ie
Naomi
N
Walsh
Susan
S
Kennedy
AnneMarie
A
Larkin
Brendan
B
Corkery
Lorraine
L
O'Driscoll
Martin
M
Clynes
John
J
Crown
Norma
N
O'Donovan
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D000077341:Lapatinib; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases