Resumen
The inhibitors of BET proteins represent a promising class of therapeutic agents that target the oncogenic activity of MYC and repress DLBCL cell migration, but the mechanism of such repression remains elusive. Herein, we found that BET inhibitor JQ1 abrogated the amoeboid movement of DLBCL cells through a small GTPase-driven mechanism, including both restrained RAS signaling and MYC-mediated suppression of GTP-RhoA activity. BET inhibition drastically increased the expression of a GTPase regulatory protein, the IQ motif containing GTPase activating protein 3 (IQGAP3), in DLBCL. Proteomics-based re-stratification identified a specific subgroup of DLBCL patients whose tumors harbored an enhanced PI3K activity and had an inferior survival, whereas a lower IQGAP3 expression level further portended a very dismal outcome for those patients. The inhibitors of both BET and RAS (through attenuated PI3K signaling) activities effectively ameliorated the outspread of in vivo DLBCL tumors, indicating the potential of their synergism in the treatment of specific DLBCL subtypes.