PMID- 25152703
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20231110
IS  - 1574-3624 (Print)
IS  - 2212-389X (Electronic)
IS  - 1574-3624 (Linking)
VI  - 8
IP  - 3
DP  - 2014 Dec
TI  - Mammalian Target of Rapamycin Inhibitors Resistance Mechanisms in Clear Cell 
      Renal Cell Carcinoma.
PG  - 210-218
AB  - Mammalian target of rapamycin (mTOR) is a kinase protein involved in PI3K/AKT 
      signaling with a central role in the processes of cell growth, survival and 
      angiogenesis. Frequent mutations of this pathway make upstream and downstream 
      components novel targets for tailored therapy design. Two mTOR inhibitors - 
      everolimus and temsirolimus - enable an increase in overall survival (OS) or 
      progression-free survival (PFS) time in a treatment of renal cancer. Despite 
      recent advances in renal cancer treatment, resistance to targeted therapy is 
      common. Understanding of molecular mechanisms is the basis of drug resistance 
      which can facilitate prediction of success or failure in combinational or 
      sequential targeted therapy. The article provides current knowledge on the mTOR 
      signaling network and gives insight into the mechanisms of resistance to mTOR 
      inhibitors from the complex perspective of RCC biology. The mechanisms of 
      resistance developed not only by cancer cells, but also by interactions with 
      tumor microenvironment are analyzed to emphasize the role of angiogenesis in 
      ccRCC pathogenesis. As recent studies have shown the role of PI3K/AKT-mTOR 
      pathway in proliferation and differentiation of cancer stem cells, we discuss 
      cancer stem cell hypothesis and its possible contribution to ccRCC resistance. In 
      the context of drug resistance, we also elaborate on a new approach considering 
      ccRCC as a metabolic disease. In conclusion we speculate on future developments 
      in agents targeting the mTOR pathway taking into consideration the singular 
      biology of ccRCC.
FAU - Kornakiewicz, Anna
AU  - Kornakiewicz A
AD  - Oncology Department, Laboratory of Molecular Oncology, Military nstitute of 
      Medicine, Warsaw, Poland ; I Faculty of Medicine, Medical University of Warsaw, 
      Poland ; Collegium Invisibile, Warsaw, Poland.
FAU - Solarek, Wojciech
AU  - Solarek W
AD  - Oncology Department, Laboratory of Molecular Oncology, Military nstitute of 
      Medicine, Warsaw, Poland ; Postgraduate School of Molecular Medicine, Medical 
      University of Warsaw, Warsaw, Poland.
FAU - Bielecka, Zofia F
AU  - Bielecka ZF
AD  - Oncology Department, Laboratory of Molecular Oncology, Military nstitute of 
      Medicine, Warsaw, Poland ; Postgraduate School of Molecular Medicine, Medical 
      University of Warsaw, Warsaw, Poland.
FAU - Lian, Fei
AU  - Lian F
AD  - Department of Urology, Emory School of Medicine, Atlanta, GA, USA.
FAU - Szczylik, Cezary
AU  - Szczylik C
AD  - Oncology Department, Laboratory of Molecular Oncology, Military nstitute of 
      Medicine, Warsaw, Poland.
FAU - Czarnecka, Anna M
AU  - Czarnecka AM
AD  - Oncology Department, Laboratory of Molecular Oncology, Military nstitute of 
      Medicine, Warsaw, Poland.
LA  - eng
PT  - Journal Article
PL  - United Arab Emirates
TA  - Curr Signal Transduct Ther
JT  - Current signal transduction therapy
JID - 101273157
PMC - PMC4141323
OTO - NOTNLM
OT  - Anti-angiogenic therapy
OT  - cancer stem cells
OT  - clear cell renal cell carcinoma
OT  - drug resistance
OT  - dual mTOR inhibitors
OT  - everolimus
OT  - temsirolimus
OT  - tumor microenvironment.
EDAT- 2014/08/26 06:00
MHDA- 2014/08/26 06:01
PMCR- 2014/08/22
CRDT- 2014/08/26 06:00
PHST- 2013/11/19 00:00 [received]
PHST- 2014/01/21 00:00 [revised]
PHST- 2014/01/29 00:00 [accepted]
PHST- 2014/08/26 06:00 [entrez]
PHST- 2014/08/26 06:00 [pubmed]
PHST- 2014/08/26 06:01 [medline]
PHST- 2014/08/22 00:00 [pmc-release]
AID - CSTT-8-210 [pii]
AID - 10.2174/1574362409666140206222746 [doi]
PST - ppublish
SO  - Curr Signal Transduct Ther. 2014 Dec;8(3):210-218. doi: 
      10.2174/1574362409666140206222746.