Co-treatment of PI3K inhibitors with temsirolimus, an optimized therapy in the treatment of cancers related to mTORs.

     The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that mediates cell growth, cell proliferation, cell motility, cell survival, gene transcription, and protein synthesis. In many human cancers, particularly those with loss of the tumor suppressor PTEN, dysregulation of the mTOR signaling can be observed, and activation of mTORs have shown the significant sensitivity to rapamycin.
     Besides rapamycin, RAD001(everolimus), AP23573 (ridaforolimus) and CCI-779 (temsirolimus) are also comfirmed to be the potent inhibitors of mTOR in vitro[1]. However, single inhibitor can only produce a certain degree of antitumor effects in the clinic, and may lead to acquired resistance by activating upstream mTORC2 and Akt after prolonged use. Therefore, researchers put more insights into how to optimize existing drugs and therapy, besides exploring novel drugs.
     The results in the paper by Yang and the partners provide us some clues about the subject. The data indicated that temsirolimus completely blocked phosphorylation of rS6, which is a downstream factor of mTORC1, in all the cells regardless of sensitivity, while sensitive and resistant cells showed the different Akt phosphorylation status that a compensatory increase in Akt phosphorylation was observed in sensitive cancer cells, but the primarily resistant cells demonstrated no Akt phosphorylation. However, BEZ235 (mTOR/PI3K inhibitor) and ZSTK474 (PI3K inhibitor) overcome the compensatory effect of Akt phosphorylation when used alone, and Co-treatment of BEZ235 or ZSTK474 with temsirolimus synergistically inhibit cell growth by inducing G1 cell cycle arrest, and promote cell death in cancer cell lines[2].
     Taken together, some PI3K inhibitors can overcome cellular resistance to mTORC1 inhibitors, thus co-treatment of BEZ235 or ZSTK474 with temsirolimus may be an optimized therapy in the treatment of cancers related to mTORs.

[1]. Sci Signal 2009 2: pe24.
[2]. PLoS ONE 6(10): e26343. doi:10.1371/journal.pone.0026343

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