Ras Signaling Pathway as a Novel Downstream Effector of Bet Inhibitors in Subduing Diffuse Large B-Cell Lymphoma Migration and Progression

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease that, in spite of the advances of immunochemotherapy, still poses a major challenge to clinicians as a significant portion of patients would ultimately succumb to the disease. Through epigenetic modulation, inhibitors of bromodomain and extra-terminal (BET) proteins represent a promising class of therapeutic agents that targets the oncogenic activity of MYC in DLBCL. In our recent work, we demonstrated that STAT3-coordinated amoeboid movement led to dissemination of DLBCL cells, and strategies aiming at suppressing DLBCL cell migration significantly reduced the tumor burden in an in vivo xenograft model. We also inadvertently identified that the BET inhibitor JQ1 could mitigate in vitro DLBCL migration in the same study, a finding later confirmed in our extension work in the same in vivo model. JQ1 was demonstrated to abrogate DLBCL migration through MYC-mediated suppression of GTP-RhoA activity. Furthermore, RNA sequencing in BET inhibitor-treated DLBCL cells unraveled additional signal aberrancy, most significantly a repressed RAS pathway activity. To explore further, we bring up this proposal to dissect the molecular impacts and functional consequences of BET inhibition in DLBCL. We aim to delineate the mechanism on BET inhibitor-endued modulation of RAS activity and its effects on DLBCL cells. We would also like to employ comprehensive transcriptomic, proteomic, and mutagenomic analyses to better re-categorize DLBCL into distinct molecular clusters, which could help us discriminate RAS pathway-activating subtypes and elucidate potential prognostic implication and mechanism-based therapeutic implication in these tumors. Lastly, potential synergy between BET inhibition and RAS attenuation will be explored. It is hopeful that these findings shall provide a scientific rationale in subtype-driven, individualized therapeutic strategy in DLBCL.

Project ID:PC10907-1542
External Project ID:MOST109-2314-B182-064-MY3