Molecules that link cancer driver genes and promoters of cell death genes produce potent killing of diffuse large B-cell lymphoma (DLBCL) cells, according to findings published in Nature.1
The effectiveness of the molecules, called transcriptional/epigenetic chemical inducers of proximity (TCIPs), in killing cancer cells could have wider implications, potentially co-opting upregulated transcription factors to induce cancer cell death. The strategy could be applied not only to treat cancer but other disorders as well, said the researchers, led by Gerald Crabtree, MD, professor of pathology and developmental biology at Stanford University.
“By making use of the intrinsic driving pathways of the cancer cell and rewiring them to activate pathways of cell death, we have introduced an approach to cancer chemotherapy that is analogous to a dominant, gain-of-function mutation in genetics,” researchers said.
Induced proximity — the principle that an effective collision between two molecules is inversely proportional to cube of the distance between them — underpins many biological processes, such as receptor function and post-translational modifications. Several years ago, Dr. Crabtree, with Stuart Schreiber, PhD, of Harvard University, made the first synthetic CIPs and used them to define biologic processes that are the result of proximity.
Two-part molecules have been used to take advantage of this principle for signal transduction and localizing proteins. More recently, Craig Crews, PhD, professor of molecular, cellular, and developmental biology at Yale University, and colleagues have used them to target proteins to the proteasome, the researchers noted.
“The observation that even an event as carefully regulated as programmed cell death can be activated by CIPs suggests that distinct cellular circuitries might be linked, or rewired, using CIPs to cause cancer cells to activate processes leading to apoptosis,” they said.
Researchers targeted DLBCL with their first TCIPs. They used a small molecule that links to the transcription factor BCL6 and inhibits its ability to interact with repressors of pro-apoptotic and cell-cycle arrest genes, effectively removing a shield against cell death that cancer cells use to survive. To boost activation of pro-apoptotic genes, they covalently linked to ligands for the transcription factor BRD4 and other transcription factors that drive tumor development through activation of the MYC oncogene.
They tested this double-link molecule, TCIP1, on the chemotherapy-resistant DLBCL cell line KARPAS422 and found that it “rapidly and robustly” killed these cells. When the small molecules were used by themselves, they found 100- to 1,000-fold less killing, which “excludes the possibility that TCIP1 acts by simply delivering two inhibitors into the cell,” they said. “The 1,000-fold increase in potency of TCIP1 over BRD4 or BCL6 degradation,” shown in in vivo and in vitro assays, “suggested the formation of a gain-of-function ternary complex between BRD4, BCL6, and TCIP1.”
Dr. Crabtree said the approach also brings therapeutic precision.
"Keeping the cell death genes and programmed cell death under the rigorous control of the cancer driver results in highly selective killing of the cancer cell with little effect upon cells that do not bear the oncogenic mutation," he said.
Other DLBCL cell lines that had no detectable BCL6 showed little or no response to TCIP1, researchers reported. In DLBCL, about 60% of patients have mutations in the non-coding region of the BCL6 gene that increase its expression.
The TCIP approach could avoid problems seen with other strategies, researchers suggested. Use of a dominant gain-of-function strategy gives extraordinary potency and does not require all of the target protein be inhibited, they said.
“Existing approaches to targeted cancer chemotherapy rely on inhibiting or degrading a protein or preventing its synthesis by RNAi or CRISPR (or CRISPRi),” researchers said. “These approaches require complete or near complete removal of the driver function, often resulting in mechanism-based toxicity when the cancer driver is an essential protein.”
In an accompanying commentary, James Phelan, PhD, and Louis Staudt, MD, PhD — who study lymphoid malignancies at the National Cancer Institute — wrote that the gain-of-function mechanism might be especially helpful for large and poorly vascularized tumors where it is hard to get high drug concentrations because only a fraction of the BCL6 needs to be engaged.2
However, they also said the complexity of the approach calls for careful vetting and clinical trials should watch for possible inflammatory side effects.
“Overall, the development of TCIPs will be limited only by the imagination of cancer biologists and the innovation of chemists,” they said. “Such efforts promise to end the perception that cancer-promoting transcription factors cannot be targeted by drugs.”
Any conflicts of interest declared by the authors can be found in the original article.
References
- Gourisankar S, Krokhotin A, Ji W, et al. Rewiring cancer drivers to activate apoptosis. Nature. 2023;620:417-425.
- Phelan JD, Staudt LM. Double-headed molecule activates cell-death pathways in cancer cells. Nature. 2023;620:285-286.