TY - JOUR
T1 - EGFR and HER2 inhibition in pancreatic cancer
AU - Walsh, Naomi
AU - Kennedy, Susan
AU - Larkin, Annemarie
AU - Corkery, Brendan
AU - O'Driscoll, Lorraine
AU - Clynes, Martin
AU - Crown, John
AU - O'Donovan, Norma
PY - 2013/6
Y1 - 2013/6
N2 - 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 (IC50 < 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.
AB - 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 (IC50 < 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.
KW - EGFR
KW - Erlotinib
KW - HER2
KW - Immunohistochemistry
KW - Lapatinib
KW - Pancreatic cancer
UR - http://www.scopus.com/inward/record.url?scp=84879079379&partnerID=8YFLogxK
U2 - 10.1007/s10637-012-9891-x
DO - 10.1007/s10637-012-9891-x
M3 - Article
C2 - 23076814
AN - SCOPUS:84879079379
SN - 0167-6997
VL - 31
SP - 558
EP - 566
JO - Investigational New Drugs
JF - Investigational New Drugs
IS - 3
ER -
