Rewiring Cancer Drivers to Activate Apoptosis

ABSTRACT: Genes that drive the proliferation, survival, invasion and metastasis of malignant cells have been identified for manyhuman cancers. Independent studies have identified cell death pathways that eliminate cells by an altruistic form of suicide. The coexistence of the cell death pathways with the driver mutations suggest that the cancer driver could be reprogrammedto activate cell death. We have invented a new class of molecules: TCIPs (Transcriptional/EpigeneticChemical 20Inducers of Proximity) that recruit the cancer driver, or a downstream transcription factor,to the promoters of cell death genesmthereby activating their expression. To develop this concept, we have focused on diffuse largeB cell lymphoma(DLBCL),in which BCL6 is amplified or mutated. BCL6 binds to the promoters of cell death genes and epigenetically suppresses their expression. We produced the first TCIPs by chemically linking BCL6 inhibitors with small molecule binders to transcriptional activators. Several of these molecules robustly kill DLBCL at single-digit nanomolar concentrations, including chemotherapy-resistant, TP53-mutant lines. The dominant gain-of-function approach provided by TCIPs allows access to therapeutic space unreachable to conventional small molecule inhibitors or degraders, RNAi,or CRISPR(i). TCIPs are relatively non-toxic to normal cells and selective in malignant cells, reflecting their need for coincident expression of both target proteins for effective killing. The later attribute should allow highly personalized treatment. The general TCIP concept has applications in elimination of senescent cells, enhancing expression of therapeutic genes, treatment of diseases produced by haploinsufficiency,and activation of immunogens for immunotherapy.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE211282 | GEO | 2023/05/03

REPOSITORIES: GEO