Huang Lianna, Chen Luping, Huang Yufei, Gao Shou-Jiang
Cancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
J Med Virol. 2025 Aug;97(8):e70534. doi: 10.1002/jmv.70534.
Primary effusion lymphoma (PEL) is a rare and aggressive B-cell malignancy caused by Kaposi's sarcoma-associated herpesvirus (KSHV), with limited treatment options and poor prognosis. KSHV-encoded proteins and miRNAs activate multiple signaling pathways that promote cell proliferation and survival. However, the heterogeneity in pathway activation and therapeutic responses among PEL cases remains poorly characterized. In this study, we investigated the activation status of key oncogenic and survival signaling pathways, including PI3K/AKT/mTOR, FOXOs and NF-κB, and assessed the efficacy of targeted inhibitors in three KSHV-positive EBV-negative PEL cell lines BC3, BCP1 and BCBL1, KSHV-negative BJAB cells, and KSHV-infected BJAB-KSHV cells. We observed heterogeneous activation of these pathways among PEL cell lines and differential sensitivity to pathway-specific inhibitors. All KSHV-infected cell lines exhibited constitutive AKT and mTORC1 activation and were sensitive to their respective inhibitors, though with varying efficacy. FOXO1 and FOXO3a, downstream targets of AKT, were frequently downregulated or inactivated by phosphorylation, consistent with AKT hyperactivation. Inhibition of FOXO1 suppressed proliferation and induced apoptosis in a cell line-specific manner. Canonical and noncanonical NF-κB pathways were differentially activated, and contributed to cell survival, as pathway-specific inhibition suppressed proliferation. Interestingly, responses to inhibitors did not always correlate with basal pathway activation levels, highlighting the complexity of PEL signaling networks. Importantly, dual PI3K/mTOR inhibitors BGT226 and Dactolisib demonstrated superior efficacy by potently inhibiting proliferation and inducing apoptosis and cell cycle arrest in all PEL cell lines, suggesting an advantage in overcoming compensatory feedback mechanisms. These findings underscore the heterogeneity of PEL and the need for personalized therapeutic strategies. Our results support the potential of combinatorial or multi-targeted approaches to improve treatment outcomes for PEL patients and warrant further preclinical and clinical investigations.
原发性渗出性淋巴瘤（PEL）是一种由卡波西肉瘤相关疱疹病毒（KSHV）引起的罕见且侵袭性的B细胞恶性肿瘤，治疗选择有限且预后较差。KSHV编码的蛋白质和微小RNA激活多种促进细胞增殖和存活的信号通路。然而，PEL病例之间信号通路激活和治疗反应的异质性仍未得到充分表征。在本研究中，我们调查了关键致癌和存活信号通路的激活状态，包括PI3K/AKT/mTOR、FOXO家族蛋白和NF-κB，并评估了靶向抑制剂在三种KSHV阳性EBV阴性PEL细胞系BC3、BCP1和BCBL1、KSHV阴性BJAB细胞以及KSHV感染的BJAB-KSHV细胞中的疗效。我们观察到这些信号通路在PEL细胞系中存在异质性激活，并且对信号通路特异性抑制剂具有不同的敏感性。所有KSHV感染的细胞系均表现出组成性的AKT和mTORC1激活，并且对各自的抑制剂敏感，尽管疗效有所不同。AKT的下游靶点FOXO1和FOXO3a经常因磷酸化而下调或失活，这与AKT的过度激活一致。抑制FOXO1以细胞系特异性方式抑制增殖并诱导凋亡。经典和非经典NF-κB信号通路被不同程度地激活，并对细胞存活有贡献，因为信号通路特异性抑制会抑制增殖。有趣的是，对抑制剂的反应并不总是与基础信号通路激活水平相关，这突出了PEL信号网络的复杂性。重要的是，双重PI3K/mTOR抑制剂BGT226和达可替尼在所有PEL细胞系中均通过有效抑制增殖、诱导凋亡和细胞周期停滞表现出卓越的疗效，这表明在克服代偿性反馈机制方面具有优势。这些发现强调了PEL的异质性以及个性化治疗策略的必要性。我们的结果支持联合或多靶点方法改善PEL患者治疗结果的潜力，并值得进一步的临床前和临床研究。
