Effects of novel TOR inhibitors on B cell differentiation (159.5)

Abstract

Abstract A promising drug target frequently disregulated in many cancers is TOR (target of rapamycin). TOR kinase functions in two complexes, TORC1 and TORC2. TORC1 is sensitive to rapamycin that acts as an allosteric inhibitor. Rapamycin and its analogs (rapalogs) are potent immunosuppressants, but have shown limited efficacy in cancer therapy. We reported in Nature Medicine (PMID:20072130) that PP242, an active-site TOR inhibitor (asTORi), has improved anti-leukemic efficacy compared to rapamycin. Unexpectedly, PP242 at anti-leukemic doses had a lesser effect in vitro on lymphocyte proliferation and in vivo on lymphocyte function. Here we present new data comparing rapamycin with asTORi using in vitro assays of B cell differentiation. asTORi treatment increased the number of IgG switching B cells and decreased the differentiation of early antibody-secreting cells. IgM secretion was also decreased with asTORi treatment. We observed similar effects when B cells were treated with an inhibitor that targets Akt, a known TORC2 substrate. Rapamycin potently inhibited B cell differentiation at an early step before commitment to cell division. Gene expression analysis revealed an increased in FOXO target genes AID and Bcl6, and a decrease in BLIMP-1 expression in asTORi-treated B cells. These data indicate that asTORi alter the balance of B cell differentiation, likely through modulation of the TORC2/Akt/FOXO signaling axis.