Proliferating Cell Nuclear Antigen as New Therapeutic Target in Multiple Myeloma

Multiple myeloma (MM), the second most common hematologic malignancy, remains incurable despite major therapeutic advances, highlighting an urgent need for novel therapeutic strategies. PCNA is involved in DNA replication and repair, chromatin remodeling, and cell-cycle progression, and increased PCNA expression has been associated with aggressive MM phenotypes and poor clinical outcomes. Cancer cells express a post-translationally modified cancer-associated isoform of PCNA (caPCNA), potentially providing a selective therapeutic target. We evaluated the anti-myeloma activity of the novel caPCNA inhibitor AOH1996 alone and in combination with established anti-myeloma agents in vitro, in vivo, and ex vivo. AOH1996 inhibited growth of multiple MM cell lines in a dose-dependent manner, induced G2-phase accumulation and apoptosis, and reduced sphere formation and colony formation capacity. Combination treatment with bortezomib, venetoclax, melphalan, or cyclophosphamide enhanced anti-myeloma activity relative to single-agent treatment. AOH1996 treatment down-regulated the expression of multiple tumor-associated proteins and inflammatory and pro-survival cytokines. miRNA analysis demonstrated suppression of several oncogenic miRNAs along with upregulation of tumor-suppressive miRNA miR-145. Forced expression of miR-145 inhibited MM cell growth and enhanced sensitivity to AOH1996, implicating miR-145 as a mechanistic mediator of PCNA inhibition's anti-tumor effects. In xenograft models, AOH1996 significantly enhanced the anti-tumor activity of bortezomib and venetoclax without apparent toxicity. Ex vivo studies demonstrated selective activity against primary MM cells and CD138+ plasma cells with minimal effects on normal PBMCs. Collectively, these findings support caPCNA as a promising therapeutic target in MM and provide strong preclinical rationale for further clinical investigation of AOH1996-based therapeutic strategies.