J Lung Cancer.  2009 Dec;8(2):92-98. 10.6058/jlc.2009.8.2.92.

Combining Erlotinib with Cytotoxic Chemotherapy May Overcome Resistance Caused by T790M Mutation of EGFR Gene in Non-Small Cell Lung Carcinoma

• Oh IJ
• Kim KS
• Jeong JY
• Cho HJ
• Kim YC

• KMID: 2199968
• DOI: http://doi.org/10.6058/jlc.2009.8.2.92

Abstract

PURPOSE
T790M is a mechanism underlying acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). We hypothesized that a synergistic combination of cytotoxic drugs and EGFR-TKIs may overcome resistance.
MATERIALS AND METHODS
The antiproliferative effects and cell cycle distributions following treatments with Erlotinib (E) and cytotoxic drugs (C) were studied using a lung cancer cell line (NCI-H1975) harboring two mutations (L858R and T790M) in the EGFR gene. The cell viability assay and cell cycle analysis were conducted via an MTT assay and flow cytometry. The results of the treatments in different sequences were assessed using the combination index.
RESULTS
Antagonisms were noted when erlotinib was administered before cytotoxic drugs (EC sequence), whereas synergisms were observed when pre-treatment with cytotoxic drugs was administered before erlotinib (CE sequence). Treatment in the EC sequence arrested the cells in G0/G1 phase and reduced the apoptotic fraction. However, treatment in the CE sequence arrested the cells in the G2/M and S phase and a trend toward higher fractions of apoptotic cell death was observed.
CONCLUSION
Our studies demonstrated a schedule-dependent effect of cytotoxic drugs and erlotinib in an NSCLC cell line with the T790M mutation. Sequential treatment may overcome EGFR-TKI resistance.

Keyword

Erlotinib; Drug therapy; Non-small-cell lung carcinoma; T790M

MeSH Terms

Carcinoma, Non-Small-Cell Lung
Cell Cycle
Cell Death
Cell Line
Cell Survival
Flow Cytometry
Genes, erbB-1
Lung
Lung Neoplasms
Protein-Tyrosine Kinases
Quinazolines
Receptor, Epidermal Growth Factor
S Phase
Erlotinib Hydrochloride
Protein-Tyrosine Kinases
Quinazolines
Receptor, Epidermal Growth Factor

Figure

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  Fig. 1. DNA histograms and percentage in cell cycles after treatment with individual drugs. Pretreatment with erlotinib (E) abrogated the effects of cytotoxic drugs. Treatment with cytotoxic drugs (paclitaxel, P; docetaxel, D; or gemcitabine, G) followed by erlotinib (E) resulted in enhanced accumulation of G2/M or S fractions.

• 

  Fig. 2. Growth-inhibitory effects of treatment with erlotinib (E) in combination with paclitaxel (T), docetaxel (D) and gemcitabine (G). Pretreatment with erlotinib exerted the least profound cytotoxic effect, whereas the administration of cytotoxic drugs followed by erlotinib exhibited the most potent cytotoxic effects. Data represent the averages of 3 different experiments, each conducted in triplicate. The Y axes represent the percentage of viable cells.

Reference

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