Rewiring cancer drivers to activate apoptosis

Sai Gourisankar, Andrey Krokhotin, Wenzhi Ji, Xiaofan Liu, Chiung-Ying Chang, Samuel H. Kim, Zhengnian Li, Wendy Wenderski, Juste M. Simanauskaite, Haopeng Yang, Hannes Vogel, Tinghu Zhang, Michael R. Green, Nathanael S. Gray () and Gerald R. Crabtree ()
Additional contact information
Sai Gourisankar: Stanford University
Andrey Krokhotin: Stanford University
Wenzhi Ji: Stanford University
Xiaofan Liu: Stanford University
Chiung-Ying Chang: Stanford University
Samuel H. Kim: Stanford University
Zhengnian Li: Stanford University
Wendy Wenderski: Stanford University
Juste M. Simanauskaite: Stanford University
Haopeng Yang: The University of Texas MD Anderson Cancer Center
Hannes Vogel: Stanford University
Tinghu Zhang: Stanford University
Michael R. Green: The University of Texas MD Anderson Cancer Center
Nathanael S. Gray: Stanford University
Gerald R. Crabtree: Stanford University

Nature, 2023, vol. 620, issue 7973, 417-425

Abstract: Abstract Genes that drive the proliferation, survival, invasion and metastasis of malignant cells have been identified for many human cancers1–4. Independent studies have identified cell death pathways that eliminate cells for the good of the organism5,6. The coexistence of cell death pathways with driver mutations suggests that the cancer driver could be rewired to activate cell death using chemical inducers of proximity (CIPs). Here we describe a new class of molecules called transcriptional/epigenetic CIPs (TCIPs) that recruit the endogenous cancer driver, or a downstream transcription factor, to the promoters of cell death genes, thereby activating their expression. We focused on diffuse large B cell lymphoma, in which the transcription factor B cell lymphoma 6 (BCL6) is deregulated7. BCL6 binds to the promoters of cell death genes and epigenetically suppresses their expression8. We produced TCIPs by covalently linking small molecules that bind BCL6 to those that bind to transcriptional activators that contribute to the oncogenic program, such as BRD4. The most potent molecule, TCIP1, increases binding of BRD4 by 50% over genomic BCL6-binding sites to produce transcriptional elongation at pro-apoptotic target genes within 15 min, while reducing binding of BRD4 over enhancers by only 10%, reflecting a gain-of-function mechanism. TCIP1 kills diffuse large B cell lymphoma cell lines, including chemotherapy-resistant, TP53-mutant lines, at EC50 of 1–10 nM in 72 h and exhibits cell-specific and tissue-specific effects, capturing the combinatorial specificity inherent to transcription. The TCIP concept also has therapeutic applications in regulating the expression of genes for regenerative medicine and developmental disorders.

Date: 2023
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DOI: 10.1038/s41586-023-06348-2

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