XPO1 inhibition by selinexor induces potent cytotoxicity against high grade bladder malignancies.

摘要: Treatment options for high grade urothelial cancers are limited and have remained largely unchanged several decades. Selinexor (KPT-330), a first in class small molecule that inhibits the nuclear export protein XPO1, has shown efficacy as single agent treatment numerous different malignancies, but its limiting bladder malignancies not been tested. In this study we assessed selinexor-dependent cytotoxicity tumor cells report selinexor effectively reduced XPO1 expression cell viability dose dependent manner. The decrease was due to an induction of apoptosis cycle arrest. These results were recapitulated vivo studies where decreased growth. Tumors treated with expressed lower levels cyclin A, B, CDK2 increased RB CDK inhibitor p27, result is consistent growth Cells expressing wildtype RB, potent suppressor promotes arrest apoptosis, most susceptible selinexor. Cell fractionation immunofluorescence showed mechanistic revealed ablation curtailed response drug. Conversely, CDK4/6 phosphorylation by palbociclib additive reducing viability, confirming activity role inhibition. provide rationale inhibition novel strategy malignancies.