Development of PDX MCL model of PRMT5 inhibitor resistance. (A) Peripheral disease burden based on circulating neoplastic cells (CD5⁺/CD19⁺) cells in the PRT-382 (red) and VC (blue) treated cohort in the PDX MCL model. One PRT-382–treated mouse became resistant to therapy as evidenced by its increased peripheral disease burden (circle), (B) increased spleen weight in resistant mouse (circle), and (C) increased neoplastic infiltration and ki67 staining of the kidney via histopathology of the PRMT5 inhibitor–resistant mouse compared with those of both VC and other PRMT5 inhibitor–sensitive mice in its cohort; H&E, original magnification ×20 and ×40 and ki67, original magnification ×40×. (D) Kaplan-Meier plot of the in vivo experiment conducted to validate the PRMT5 inhibitor–resistant mouse. There is decreased survival (P = .005) despite PRT-382 treatment in mice engrafted with PRMT5 inhibitor–resistant (purple) vs PRMT5 inhibitor–naive (green) cells. Mice were engrafted on day 0 and treatment initiated on day 43 when PRT-382 10 mg/kg or vehicle was administered by mouth 4 days on and 3 days off. MS for PRMT5 inhibitor–resistant and –naive engrafted vehicle, 65 days; for PRMT5 inhibitor–resistant engrafted PRT-382, 71 days; and for PRMT5 inhibitor–naive engrafted PRT-382, 77 days. Unless otherwise indicated, significance is relative to the PRMT5 inhibitor–naive engrafted VC cohort; ∗∗P < .01. H&E, hematoxylin and eosin.