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

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.