Inhibition of RPTOR overcomes resistance to EGFR inhibition in triple-negative breast cancer cells

  • Authors:
    • Kyu Sic You
    • Yong Weon Yi
    • Sahng-June Kwak
    • Yeon-Sun Seong
  • View Affiliations

  • Published online on: January 15, 2018     https://doi.org/10.3892/ijo.2018.4244
  • Pages: 828-840
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Abstract

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.
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March-2018
Volume 52 Issue 3

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
You KS, Yi YW, Kwak S and Seong Y: Inhibition of RPTOR overcomes resistance to EGFR inhibition in triple-negative breast cancer cells. Int J Oncol 52: 828-840, 2018
APA
You, K.S., Yi, Y.W., Kwak, S., & Seong, Y. (2018). Inhibition of RPTOR overcomes resistance to EGFR inhibition in triple-negative breast cancer cells. International Journal of Oncology, 52, 828-840. https://doi.org/10.3892/ijo.2018.4244
MLA
You, K. S., Yi, Y. W., Kwak, S., Seong, Y."Inhibition of RPTOR overcomes resistance to EGFR inhibition in triple-negative breast cancer cells". International Journal of Oncology 52.3 (2018): 828-840.
Chicago
You, K. S., Yi, Y. W., Kwak, S., Seong, Y."Inhibition of RPTOR overcomes resistance to EGFR inhibition in triple-negative breast cancer cells". International Journal of Oncology 52, no. 3 (2018): 828-840. https://doi.org/10.3892/ijo.2018.4244