PMID- 29344641
OWN - NLM
STAT- MEDLINE
DCOM- 20180831
LR  - 20211204
IS  - 1791-2423 (Electronic)
IS  - 1019-6439 (Linking)
VI  - 52
IP  - 3
DP  - 2018 Mar
TI  - Inhibition of RPTOR overcomes resistance to EGFR inhibition in triple-negative 
      breast cancer cells.
PG  - 828-840
LID - 10.3892/ijo.2018.4244 [doi]
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.
FAU - You, Kyu Sic
AU  - You KS
AD  - Graduate School of Convergence Medical Science, Dankook University, Cheonan 
      31116, Republic of Korea.
FAU - Yi, Yong Weon
AU  - Yi YW
AD  - ExoCoBio Inc, Seoul 08594, Republic of Korea.
FAU - Kwak, Sahng-June
AU  - Kwak SJ
AD  - Department of Biochemistry, College of Medicine, Dankook University, Cheonan 
      31116, Republic of Korea.
FAU - Seong, Yeon-Sun
AU  - Seong YS
AD  - Graduate School of Convergence Medical Science, Dankook University, Cheonan 
      31116, Republic of Korea.
LA  - eng
PT  - Journal Article
DEP - 20180115
PL  - Greece
TA  - Int J Oncol
JT  - International journal of oncology
JID - 9306042
RN  - 0 (Heterocyclic Compounds, 3-Ring)
RN  - 0 (MK 2206)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Quinazolines)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (RPTOR protein, human)
RN  - 0 (Regulatory-Associated Protein of mTOR)
RN  - 0 (Ribosomal Protein S6)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.10.1 (EGFR protein, human)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - S65743JHBS (Gefitinib)
SB  - IM
MH  - Antineoplastic Combined Chemotherapy Protocols/*pharmacology/therapeutic use
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Down-Regulation
MH  - Drug Resistance, Neoplasm/*drug effects
MH  - Drug Screening Assays, Antitumor
MH  - Drug Synergism
MH  - ErbB Receptors/antagonists & inhibitors/metabolism
MH  - Female
MH  - Gefitinib
MH  - Gene Knockdown Techniques
MH  - Heterocyclic Compounds, 3-Ring/pharmacology
MH  - Humans
MH  - Protein Kinase Inhibitors/*pharmacology/therapeutic use
MH  - Proto-Oncogene Proteins c-akt/antagonists & inhibitors
MH  - Quinazolines/pharmacology/therapeutic use
MH  - RNA, Small Interfering/metabolism
MH  - Regulatory-Associated Protein of mTOR/genetics/*metabolism
MH  - Ribosomal Protein S6/metabolism
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors
MH  - Triple Negative Breast Neoplasms/*drug therapy/pathology
EDAT- 2018/01/19 06:00
MHDA- 2018/09/01 06:00
CRDT- 2018/01/19 06:00
PHST- 2017/09/14 00:00 [received]
PHST- 2018/01/08 00:00 [accepted]
PHST- 2018/01/19 06:00 [pubmed]
PHST- 2018/09/01 06:00 [medline]
PHST- 2018/01/19 06:00 [entrez]
AID - 10.3892/ijo.2018.4244 [doi]
PST - ppublish
SO  - Int J Oncol. 2018 Mar;52(3):828-840. doi: 10.3892/ijo.2018.4244. Epub 2018 Jan 
      15.