YX0798 is effective in inhibiting the tumor growth of PDX models in vivo. (A) Four primary samples originating from patients with BTKi-R/R MCL were confirmed to be resistant to BTKi PBN, (B) but were sensitive to CDK9is AZD4573 and YX0798. (C) YX0798 treatment for 6 hours inhibited CDK9 phosphorylation and induced cleavage of PARP, as well as MCL-1 depletion, in a dose-dependent manner in primary samples obtained from a patient with PBN-R. (D) CDK9is, such as AZD4573 or YX0798 (but not BTKis PBN or acalabrutinib), inhibited the growth of PDO models, which originated from the same patient samples used in panel C. (E-G) PDX models were established from a patient with sequential relapse to ibrutinib and CAR T-cell therapies. YX0798 was orally administered at 5 mg/kg (5 days on and 2 days off every week, equivalent to 25 mg/kg per week), whereas AZD4573 was intraperitoneally (IP) administered at 15 + 15 mg/kg (2 doses at 2 hours apart, once a week, equivalent to 30 mg/kg per week). (E) YX0798 treatment significantly inhibited tumor growth and (F) prolonged mouse survival. (G) Treatment with AZD4573 or YX0798 did not affect mouse body weight. ∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001. ns, not significant; p-CDK9, phosphorylated cyclin-dependent kinase 9; PBN, pirtobrutinib; PBN-R, pirtobrutinib resistance; PT, patient.
Figure 4.

YX0798 is effective in inhibiting the tumor growth of PDX models in vivo. (A) Four primary samples originating from patients with BTKi-R/R MCL were confirmed to be resistant to BTKi PBN, (B) but were sensitive to CDK9is AZD4573 and YX0798. (C) YX0798 treatment for 6 hours inhibited CDK9 phosphorylation and induced cleavage of PARP, as well as MCL-1 depletion, in a dose-dependent manner in primary samples obtained from a patient with PBN-R. (D) CDK9is, such as AZD4573 or YX0798 (but not BTKis PBN or acalabrutinib), inhibited the growth of PDO models, which originated from the same patient samples used in panel C. (E-G) PDX models were established from a patient with sequential relapse to ibrutinib and CAR T-cell therapies. YX0798 was orally administered at 5 mg/kg (5 days on and 2 days off every week, equivalent to 25 mg/kg per week), whereas AZD4573 was intraperitoneally (IP) administered at 15 + 15 mg/kg (2 doses at 2 hours apart, once a week, equivalent to 30 mg/kg per week). (E) YX0798 treatment significantly inhibited tumor growth and (F) prolonged mouse survival. (G) Treatment with AZD4573 or YX0798 did not affect mouse body weight. ∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001. ns, not significant; p-CDK9, phosphorylated cyclin-dependent kinase 9; PBN, pirtobrutinib; PBN-R, pirtobrutinib resistance; PT, patient.

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