Mol Cancer Res. 2020 Nov 5:molcanres.0466.2020. doi: 10.1158/1541-7786.MCR-20-0466. Online ahead of print.
Diffuse large B-cell lymphoma (DLBCL) is the major type of aggressive B-cell lymphoma. High-grade B-cell lymphoma (HGBCL) with MYC/BCL2 double-hit (DH) represents a distinct entity with dismal prognosis after standard immunochemotherapy in the current WHO lymphoma classification. However, whether TP53 mutation synergizes with MYC abnormalities (MYC rearrangement and/or Myc protein overexpression) contributing to HGBCL-like biology and prognosis is not well investigated. In this study, DLBCL
patients with MYC/TP53 abnormalities demonstrated poor clinical outcome, high-grade morphology, and distinct gene-expression signatures. To identify more effective therapies for this distinctive DLBCL subset, novel MYC/TP53/BCL-2 targeted agents were investigated in DLBCL cells with MYC/TP53 dual alterations or HGBCL-MYC/BCL2-DH. A BET inhibitor INCB057643 effectively inhibited cell viability and induced apoptosis in DLBCL/HGBCL cells regardless of MYC/BCL2/TP53 status. Combining INCB057643 with a MDM2-p53 inhibitor DS3032b significantly enhanced cytotoxicity in HGBCL-DH without TP53 mutation, while combining with the BCL-2 inhibitor venetoclax displayed potent therapeutic synergy in DLBCL/HGBCL cells with and without concurrent TP53 mutation. Reverse-phase protein arrays revealed the synergistic molecular actions by INCB057643, DS3032b and venetoclax to induce cell cycle arrest and apoptosis and to inhibit AKT/MEK/ERK/mTOR pathways, as well as potential drug-resistance mechanisms mediated by upregulation of MCL-1 and RAS/RAF/mTOR pathways. In summary, these findings support sub-classification of DLBCL/HGBCL with dual MYC/TP53 alterations which demonstrates distinct pathobiological features and dismal survival with standard therapy therefore requiring additional targeted therapies. Implications: The clinical and pharmacologic studies suggest recognizing DLBCL with concomitant TP53 mutation and MYC abnormalities as a distinctive entity necessary for precision oncology practice.