Mammalian Target of Rapamycin Inhibitors Resistance Mechanisms in Clear Cell Renal Cell Carcinoma
Anna Kornakiewicz, Wojciech Solarek, Zofia F. Bielecka, Fei Lian, Cezary Szczylik and Anna M. Czarnecka
Affiliation: Oncology Department, Laboratory of Molecular Oncology, Military Institute of Medicine, Szaserów 128, 04-141 Warsaw, Poland.
Keywords: Anti-angiogenic therapy, cancer stem cells, clear cell renal cell carcinoma, drug resistance, dual mTOR inhibitors,
everolimus, temsirolimus, tumor microenvironment.
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.
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