Targeting Hyaluronan Signaling Overcomes Primary Effusion Lymphoma Cells Resistance to Rapamycin

The oncogenic γ-herpesvirus known as the Kaposi's sarcoma-associated herpesvirus (KSHV) is a principal causative agent of several cancers arising in patients with compromised immune systems. One of KSHV-related malignancies, primary effusion lymphoma (PEL), comprises transformed B cells harboring the viral episome and arises preferentially within the pleural or peritoneal cavities of patients including those with HIV infection. PEL is a rapidly progressing malignancy with a median survival time of several months even with conventional chemotherapy. One of the major reasons causing PEL chemotherapy failure is multidrug chemoresistance of lymphoma cells, however, there are only limited data exploring the mechanisms of PEL chemoresistance. In the current study, we demonstrate the role of hyaluronan (HA) signaling activation in rapamycin resistance in PEL cells, and that targeting HA signaling by small HA oligosaccharides (oHA) can augment rapamycin efficacy against PEL expansion in vivo. Our results provide the framework for the development of HA-targeted therapies clinical trials for PEL patients, which may represent promising adjuncts to reduce chemotherapy toxicity, improve treatment and prolong patients' survival.