Fig. 9

Mechanism-based combinatorial experimental regimens aimed at disrupting known oncogenic cooperation pathways in ABC-DLBCLs. Targets for rational mechanism-based combinatorial experimental regimens are shown for ABC-DLBCL (a and b). The black thick lines connecting the different drug targets pathways depict established biological interactions and/or dependencies. The single drugs listed in (a) have either proven clinical activity in patients with DLBCL or are currently in clinical trials for patients with B-cell lymphoma, including DLBCL. Pathways in ABC-DLBCL targeted by rational drug combinations using drugs tested as single agent in preclinical studies or clinical trials are shown in (b). Bortezomib and carfilzomib inhibit the 26S proteasome complex thereby blocking the degradation of negative regulators of cell cycle progression as well as of NF-κB inhibitory protein IκBα. Lenalidomide is an immunomodulatory agent directly binding to the E3 ubiquitin ligase substrate receptor CRBN and promoting the recruitment of its common substrates to the E3 ubiquitin ligase complex, thus leading to substrate ubiquitinylation and degradation [284] and subsequent repression of IRF4, a hallmark of ABC-DLBCL cells, thereby inhibiting the BCR-mediated canonical NF-κB-dependent pro-survival signaling pathways [90, 91]. Silvestrol inhibits RNA helicase and translation initiationfactor eIF4A thereby blocking translation (i.e., of oncogenic factors) [647]. Azacytidine (AZA) and decitabine/5-aza-2′-deoxycytidine (DAC/5-AZA) inhibit DNA methyltransferases (mainly DMNT1 and DMNT3) resulting in the re-expression of tumor-suppressor genes [419, 420]. Mechanism-based drug combinations targeting the biological interaction between MYC and BCL2 as well as MYC and the PI3K/AKT/mTORC1 pathway are aimed for both GCB- and ABC-DLBCL. Adapted from REF: [590, 591]. Information for this figure was gleaned from the following references: [2, 3, 13, 16–18, 20, 29, 31, 54, 57, 60, 65, 66, 75–81, 87, 90, 91, 93, 96–100, 103, 104, 107, 123, 133, 148, 171, 232, 233, 242, 247–250, 255, 257, 266, 270, 271, 285, 286, 289, 296, 297, 307–311, 313–317, 319, 323, 324, 326, 327, 360–365, 367, 374, 375, 377, 380–382, 384–386, 388, 393, 394, 398–402, 407, 415–417, 601, 602, 612, 620, 648–652]. See also Additional file 1: Table S2 and S5–S9. Abbreviations: BCR B cell receptor, BTK Bruton’s tyrosine kinase, CD40L CD40 ligand, JAK Janus kinase, CRBN cereblon, IRF4 interferon-regulatory factor 4, MALT1 mucosa-associated lymphoid tissue lymphoma translocation protein 1, BCL10 B cell lymphoma protein 10, TLR Toll-like receptor, MyD88 myeloid differentiation primary response 88, CARD11 caspase recruitment domain family, member 11, PKCβ protein kinase Cβ, IKK inhibitor kappa B (IκB) kinase, NF-κB nuclear factor-kappa B, NIK NF-κB inducing kinase, STAT signal transducer and activator of transcription, PI3K phosphoinositide 3-kinase, mTORC1 mammalian target of rapamycin (mTOR) complex 1, BCL2 B-cell lymphoma protein 2, BCL6 B-cell lymphoma protein 6, TGFβR transforming growth factor beta (TGFβ) receptor, HDACi inhibitors of histone deacetylases, BCL6i inhibitors of BCL6, PD-1 programmed cell death, PD-L1 programmed cell death ligand, AZA azacytidine, DAC decitabine