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

Christopher M. Mahaffey, Angela M. Davies, Primo N Lara, Brandi Pryde, William Holland, Philip Mack, Paul H. Gumerlock, David R Gandara

Research output: Contribution to journalArticle

71 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)548-553
Number of pages6
JournalClinical Lung Cancer
Volume8
Issue number9
DOIs
StatePublished - Nov 2007

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Keywords

  • Epidermal growth factor receptor
  • Poly (ADP-ribose) polymerase
  • Tyrosine kinase inhibitors

ASJC Scopus subject areas

  • Cancer Research
  • Pulmonary and Respiratory Medicine

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