TY - JOUR
T1 - Schedule-dependent apoptosis in K-ras mutant non-small-cell lung cancer cell lines treated with docetaxel and erlotinib
T2 - Rationale for pharmacodynamic separation
AU - Mahaffey, Christopher M.
AU - Davies, Angela M.
AU - Lara, Primo N
AU - Pryde, Brandi
AU - Holland, William
AU - Mack, Philip
AU - Gumerlock, Paul H.
AU - Gandara, David R
PY - 2007/11
Y1 - 2007/11
N2 - BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) given concurrently with chemotherapy in 4 large randomized clinical trials did not improve patient outcomes compared with chemotherapy alone in advanced non-small-cell lung cancer (NSCLC). We hypothesized that the lack of benefit resulted from a negative interaction between chemotherapy and EGFR TKIs. MATERIALS AND METHODS: Herein, we report the cell cycle and apoptotic effects of treatment with erlotinib and docetaxel in the NSCLC cell lines A549 and Calu-1, both of which are mutant for K-ras and wild-type for EGFR. RESULTS: Treatment with erlotinib resulted in accumulation of cells in G1 phase in A549 cells, with no evidence of apoptosis. Docetaxel treatment led to apoptosis as assessed by increased sub-G1 DNA content and cleavage of caspase 3 and poly (ADP-ribose) polymerase. The sequence of docetaxel followed by erlotinib resulted in significantly enhanced apoptosis compared with single-agent docetaxel in both cell lines. However, in the reverse sequence of erlotinib followed by docetaxel, a reduction of apoptosis was observed. We hypothesize that cell cycle arrest induced by erlotinib accounts for these findings in the presence of wild-type EGFR and that pharmacodynamic separation of the 2 drug classes will ameliorate these effects. CONCLUSION: These studies provide a rationale for intermittent dosing of EGFR TKIs with chemotherapy in order to enhance cytotoxicity.
AB - BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) given concurrently with chemotherapy in 4 large randomized clinical trials did not improve patient outcomes compared with chemotherapy alone in advanced non-small-cell lung cancer (NSCLC). We hypothesized that the lack of benefit resulted from a negative interaction between chemotherapy and EGFR TKIs. MATERIALS AND METHODS: Herein, we report the cell cycle and apoptotic effects of treatment with erlotinib and docetaxel in the NSCLC cell lines A549 and Calu-1, both of which are mutant for K-ras and wild-type for EGFR. RESULTS: Treatment with erlotinib resulted in accumulation of cells in G1 phase in A549 cells, with no evidence of apoptosis. Docetaxel treatment led to apoptosis as assessed by increased sub-G1 DNA content and cleavage of caspase 3 and poly (ADP-ribose) polymerase. The sequence of docetaxel followed by erlotinib resulted in significantly enhanced apoptosis compared with single-agent docetaxel in both cell lines. However, in the reverse sequence of erlotinib followed by docetaxel, a reduction of apoptosis was observed. We hypothesize that cell cycle arrest induced by erlotinib accounts for these findings in the presence of wild-type EGFR and that pharmacodynamic separation of the 2 drug classes will ameliorate these effects. CONCLUSION: These studies provide a rationale for intermittent dosing of EGFR TKIs with chemotherapy in order to enhance cytotoxicity.
KW - Epidermal growth factor receptor
KW - Poly (ADP-ribose) polymerase
KW - Tyrosine kinase inhibitors
UR - http://www.scopus.com/inward/record.url?scp=37349080007&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=37349080007&partnerID=8YFLogxK
U2 - 10.3816/CLC.2007.n.041
DO - 10.3816/CLC.2007.n.041
M3 - Article
C2 - 18186959
AN - SCOPUS:37349080007
VL - 8
SP - 548
EP - 553
JO - Clinical Lung Cancer
JF - Clinical Lung Cancer
SN - 1525-7304
IS - 9
ER -