Cotargeting mTOR and PRMT5 confers a survival advantage in PRMT5 inhibitor PDX resistant MCL model. (A) Kaplan-Meier plot for the in vivo experiment conducted to validate combination therapy in the PRMT5 inhibitor–resistant PDX mouse model. Mice were engrafted with splenic lymphocytes from the PRMT5 inhibitor–resistant MCL PDX on day 0 and treatment initiated on day 10 with temsirolimus (12.5 mg/kg) or vehicle administered intraperitoneally weekly and PRT-808 (10 mg/kg) or vehicle chow administered in intervals (5 days on/2 days off). MS was as follows: for VC (n = 7), 54 days; for PRT 808 (n = 7), 61 days; temsirolimus (n = 8), 63 days; and combination (n = 10), 69 days. ∗ P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗ P < .0001. (B) Protein evaluation of SDMA and p-P70S6k across the 4 treatment conditions. Protein levels were normalized to VC group and indicated significance is relative to the VC. ∗ P < .05; ∗∗P < .01; ∗∗∗P < .001. GAPDH, glyceraldehyde-3-phosphate dehydrogenase.