Schedule-dependent apoptosis in K-ras mutant non-small-cell lung cancer cell lines treated with docetaxel and erlotinib: rationale for pharmacodynamic separation.
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.


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 G(1) 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.


CONCLUSIONS
These studies provide a rationale for intermittent dosing of EGFR TKIs with chemotherapy in order to enhance cytotoxicity.
Mahaffey
Christopher M
CM
University of California Davis Cancer Center, Sacramento, CA 95817, USA. angela.davies@ucdmc.ucdavis.edu
Davies
Angela M
AM
Lara
Primo N
PN
Pryde
Brandi
B
Holland
William
W
Mack
Philip C
PC
Gumerlock
Paul H
PH
Gandara
David R
DR
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride; D011905:Genes, ras; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009154:Mutation; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
D011799:Quinazolines; D043823:Taxoids; D000077143:Docetaxel; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors