Diffuse large B-cell lymphoma (DLBCL) is mostly curable by chemotherapy, but p53 mutations limit the therapeutic effect of DLBCL. Although chimeric antigen receptor (CAR) T cells have made revolutionary progress in the treatment of DLBCL, p53 mutations still lead to drug resistance and/or relapse of DLBCL, affecting the prognosis of lymphoma. Therefore, the project aims to explore additional therapeutic strategies to improve the prognosis of DLBCL with p53 mutations.
Methods:
We investigated the correlation between XPO1 and mut-P53 employing qRT-PCR, WB, CCK8 and flow cytometry. Then, we conduct XPO1 inhibitor (KPT-330) to explore the apoptotic effect on DLBCL. Through the TCGA database, there is a clear correlation between XPO1-related genes and the PI3K-AKT pathway.
Results:
In this study, we showed that XPO1 inhibitor (KPT-330) synergized with CAR-T to reduce the viability of DLBCL and enhance the killing effect of CAR-T cells. As expected, KPT-330 combined with CAR-T therapy slowed tumor growth and reduced tumor burden in DLBCL with p53 mutations. Mechanistically, XPO1 inhibitor KPT-330 can cooperate with CAR-T in the treatment of DLBCL by activating the PI3K pathway. Then, in vitro cytotoxicity assays revealed that the KPT-330 combined with CAR-T group significantly enhanced the secretion of effector cytokines IFN-γ, TNF-α, and IL-2, and activated the immune system.
Conclusions:
The XPO1 inhibitor KPT-330 exerts anti-cancer effects through stabilizing p53 and inhibiting the PI3K-AKT pathway, providing a molecular basis for DLBCL treatment. We may provide a potential promising combination therapy for the treatment of DLBCL with p53 mutations.
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