Targeting RAB7 in human B lymphoma by a small molecule inhibitor arrests tumor cell growth

RAB7, encoded by <i>RAB7A</i> in humans and <i>Rab7</i> in mice, is a small GTPase that catalyzes endosome maturation. It mediates NF-κB activation through the assembly of intracellular membrane signalosomes in stimulated normal B cells and plays a B cell-intrinsic role in the antibody response in mice. Here we show <i>RAB7A</i> transcripts are expressed in primary diffuse large B-cell lymphomas (DLBCLs), and that RAB7 protein expression is heightened in activated human tonsil B cells as well as in DLBCL and Burkitt lymphoma cell lines. Treating these cell lines with CID1067700, a selective small-molecule RAB7 inhibitor, results in a dose-dependent decrease in cell growth, associated with impaired proliferation and survival. CID1067700 also suppressed tumor development from Daudi cells, a Burkitt lymphoma cell line, in <i>Foxn1^nu/nu</i> nude mice. The inhibitory effect of CID1067700 on Daudi cell growth <i>in vitro</i> is further enhanced by methyl-β-cyclodextrin, which disrupts plasma membrane lipid rafts, and by FX1, a BCL6 inhibitor. These findings, together with the unfavorable prognosis of DLBCL patients showing high <i>RAB7A</i> expression, suggest that targeting RAB7 is a promising therapeutic approach for mature B cell-derived lymphomas.