XPO1 inhibitor selinexor enhances the apoptotic effect of azacitidine in T-cell lymphoma with TET2/RHOA mutations via JAK3/STAT3 axis.

BACKGROUND: Peripheral T-cell lymphoma (PTCL) is a highly heterogeneous group of lymphoid malignancies with diverse pathological and molecular features. Patients harboring TET2 and RHOA double mutations exhibit poor response to anthracycline-based chemotherapy and unfavorable prognosis. Azacitidine, a hypomethylating agent, is frequently used in combination with anthracycline-based regimens in PTCL. However, resistance remains a significant challenge. This study aims to explore novel targeted therapies to overcome therapeutic resistance in TET2/RHOA-mutated PTCL patients. METHODS: A systematic screen of 633 anti-tumor compounds was conducted to identify synergistic agents with azacitidine in TET2/RHOA-mutated cells. Cell viability assays, apoptosis analyses, and zebrafish xenograft models were performed to evaluate synergy. Cell-line derived xenograft (CDX) murine models were established to assess in vivo efficacy. RNA-sequencing, western blotting, and immunohistochemical staining were applied to elucidate the underlying mechanisms. A clinical case of TET2/RHOA-mutated PTCL treated with combination therapy was reported and analyzed. RESULTS: Selinexor, an XPO1 inhibitor, was identified as a potent synergistic agent with azacitidine, significantly enhancing anti-tumor effects across multiple preclinical models. The combination inhibited T-lymphoma proliferation and induced apoptosis, associated with suppression of the JAK3/STAT3 pathway. Mechanistically, azacitidine upregulated negative regulators such as SOCS1, while selinexor sequestered STAT3 in the nucleus and reduced phosphorylated STAT3. In CDX models, the combination treatment markedly reduced tumor burdens. A clinical case of TET2/RHOA-mutated PTCL showed favorable outcomes upon this combination therapy, supporting the translational potential. CONCLUSIONS: Selinexor and azacitidine offer a promising strategy to overcome therapeutic resistance and improve outcomes in TET2/RHOA-mutated PTCL, supporting further clinical evaluation.