Cotargeting mTOR and PRMT5 results in synergistic reduction in cell proliferation in PRMT5 inhibitor–resistant MCL cell line models. (A) IC50 curves measured via MTS after 72 hours of temsirolimus treatment in resistant and sensitive MCL cell lines (SP53 and Z-138). (B) Synergy matrixes for the PRMT5 inhibitor (PRT-382) and mTORC1 Inhibitor (temsirolimus) were calculated with Combenefit via the Lowe model of synergy (x < −10 = antagonistic; −10 < x < 10 = additive; x > 10 = synergistic); ∗P < .05; ∗∗P < .01; ∗∗∗ P < .001. Drugging was conducted with 6 days of PRT-382, followed by 3 days of PRT-382 with and without temsirolimus. (C) p-p70S6k protein levels at baseline in PRMT5 inhibitor–sensitive and -resistant MCL cell lines. (D) Total and p-p70S6k protein levels by treatment condition in SP53 and Z-138 resistant and sensitive cell lines. Drugging was conducted for 3 days with or without PRT-382, followed by 3 days with or without PRT-382 and/or temsirolimus. Protein levels were normalized to the untreated sensitive cell condition.
