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 combi nation of cytotoxic drugs and EGFR- TKIs m ay overcome resistance. Materials and Methods: The antiproliferative effects and cell cycle distributions followi ng treatm ents w ith Erlotinib (E) and cytotoxic drugs (C) were studied using a lung cancer cell line (NCI-H1975) harboring tw o m utations (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 com bination index. Results: Antagonisms w ere noted w hen erlotinib w as administered before cytotoxic drugs (EC sequence), whereas synergisms were observed w hen pre-treatm ent w ith cytotoxic drugs w as admi nistered before erlotinib (C E sequence). Treatm ent in the EC sequence arrested the cells in G 0/G 1 phase and reduced the apoptotic fraction. H owever , treatm ent 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.