TY - JOUR AB - Triple-negative breast cancer (TNBC) cells frequently exhibit activated growth factor signaling and resistance to inhibitors for epidermal growth factor receptor (EGFR), despite the overexpression of EGFR protein, and this is associated with a malignant behavior and a poor prognosis. In this study, to elucidate the underlying mechanisms of resistance to EGFR inhibitor and identify inhibitors that exert a synergistic effect with EGFR inhibition, we examined the inhibitory effects of selected protein kinase inhibitors (PKIs) in combination with gefitinib on the viability of a mesenchymal stem-like (MSL) subtype TNBC cell line. MK‑2206, an AKT inhibitor, and a group of mammalian target of rapamycin (mTOR) inhibitors were found to exert synergistic lethal effects in combination with gefitinib in MDA‑MB‑231 cells. The combination of gefitinib/MK‑2206 exerted a prominent synergistic lethal effect in an MTT cell viability assay and a growth inhibitory effect in a long-term colony-forming assay in 2 MSL subtype TNBC cell lines (MDA‑MB‑231 and HS578T) and one basal-like (BL) subtype TNBC cell line (MDA‑MB-468). Gefitinib/MK‑2206 treatment synergistically decreased the mTOR signaling target substrates along with the downregulation of ribosomal protein S6 (RPS6), a marker of cell proliferation and target substrate of the AKT-mTOR signaling pathway. In addition, gefitinib markedly reduced the viability of MDA‑MD‑231 and HS578T cells when regulatory-associated protein of mTOR (RPTOR) was suppressed by siRNA-based knockdown (KD). These results thus suggest that RPTOR mediates, at least partially, the resistance to EGFR inhibition in TNBC cells. Therefore, targeting the mTOR complex 1 (mTORC1) pathway may be a potential strategy for the treatment of EGFR-resistant TNBC. AD - Graduate School of Convergence Medical Science, Dankook University, Cheonan 31116, Republic of Korea ExoCoBio Inc, Seoul 08594, Republic of Korea Department of Biochemistry, College of Medicine, Dankook University, Cheonan 31116, Republic of Korea AU - You,Kyu,Sic AU - Yi,Yong,Weon AU - Kwak,Sahng-June AU - Seong,Yeon-Sun DA - 2018/03/01 DO - 10.3892/ijo.2018.4244 EP - 840 IS - 3 JO - Int J Oncol KW - triple-negative breast cancer epidermal growth factor receptor gefitinib MK‑2206 synthetic lethal regulatory-associated protein of mTOR mTOR complex 1 PY - 2018 SN - 1019-6439 1791-2423 SP - 828 ST - Inhibition of RPTOR overcomes resistance to EGFR inhibition in triple-negative breast cancer cells T2 - International Journal of Oncology TI - Inhibition of RPTOR overcomes resistance to EGFR inhibition in triple-negative breast cancer cells UR - https://doi.org/10.3892/ijo.2018.4244 VL - 52 ER -