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. 2015 Jul 15;121(19):3481–3490. doi: 10.1002/cncr.29422

Figure 3.

Figure 3

Dose‐related plasma biomarker inhibition. Following a single dose of CC‐223 on day −1, cycle 1, inhibition (post‐dose assessments relative to the baseline value) of (A) pS6RP, (B) p4EBP1, and (C) pAKT in stimulated peripheral blood B cells, T cells, and monocytes, respectively, was observed in all patients following doses ranging from 30 to 60 mg. The phosphorylation of AKT (for mTORC2 activity) and p4EBP1 and pS6RP (mTORC1 activity) in relevant cell types were evaluated using flow cytometry with specific antibodies and expressed as equivalent reference fluorophore, ERF. (D) Model of CC‐223 mechanism of action. CC‐223 inhibits phosphorylation of 4EBP1, S6RP, and AKT through suppression of both mTORC1 and mTORC2. Abbreviations: 4EBP1, 4E–binding protein 1; AKT, protein kinase B; mTORC1, mammalian target of rapamycin complex 1; mTORC2, mammalian target of rapamycin complex 2; p4EBP1, phosphorylated 4E‐binding protein 1; p70S6K, p70 S6 kinase 1; pAKT, phosphorylated protein kinase B; PDK1, 3‐phosphoinositide‐dependent protein kinase 1; PI3K, phosphoinositide 3‐kinase; pS6RP, phosphorylated S6 ribosomal protein; S6RP, S6 ribosomal protein.