A new technique signals blood cancer cells to self-destruct like apoptosis with very high specifity

Good news! Cancer is history (soon)! Only a dead cancer cell is a good cancer cell!

Very interesting approach!

However, this research has only "therapeutic potential" and/or is very early stage so far!

"... They aim to use this natural method of cell death to trick cancer cells into disposing of themselves. Their method accomplishes this by artificially bringing together two proteins in such a way that the new compound switches on a set of cell death genes, ultimately driving tumor cells to turn on themselves. The researchers describe their latest such compound in a paper published Oct. 4 in Science. ...

One of these proteins, BCL6, when mutated, drives the blood cancer known as diffuse large cell B-cell lymphoma. This kind of cancer-driving protein is also referred to as an oncogene. In lymphoma, the mutated BCL6 sits on DNA near apoptosis-promoting genes and keeps them switched off, helping the cancer cells retain their signature immortality.

The researchers developed a molecule that tethers BCL6 to a protein known as CDK9, which acts as an enzyme that catalyzes gene activation, in this case, switching on the set of apoptosis genes that BCL6 normally keeps off. ...

When the team tested the molecule in diffuse large cell B-cell lymphoma cells in the lab, they found that it indeed killed the cancer cells with high potency. ...

Because the technique relies on the cells’ natural supply of BCL6 and CDK9 proteins, it seems to be very specific for the lymphoma cells — the BCL6 protein is found only in this kind of lymphoma cell and in one specific kind of B cell. The researchers tested the molecule in 859 different kinds of cancer cells in the lab; the chimeric compound killed only diffuse large cell B-cell lymphoma cells. ..."

From the editor's summary and abstract:

"Editor’s summary

Most drugs targeting kinases are designed to inhibit these enzymes, but there are certain situations in which it would be better to increase or retarget kinase activity instead. Sarott et al. designed a molecule to activate the transcription of key genes that are normally repressed in a particular human B cell lymphoma. In the cancer cells, transcription of these genes was inhibited by overactivity of the transcription factor BCL6 and its epigenetic co-repressors. The authors used a molecule linking an inhibitor of protein kinase CDK9 with a ligand of BCL6 to guide CDK9 and BCL6 into proximity at target genes. CDK9 was apparently released from the inhibitor complex sufficiently to phosphorylate RNA polymerase II and enhance transcriptional elongation. In a mouse model, this occurred with specificity for B cells responding abnormally to BCL6 without changing the overall activity of CDK9. Thus, repurposing protein kinase inhibitors to be part of such proximity inducers could have therapeutic potential. ...
Absract

Kinases are critical regulators of cellular function that are commonly implicated in the mechanisms underlying disease. Most drugs that target kinases are molecules that inhibit their catalytic activity, but here we used chemically induced proximity to convert kinase inhibitors into activators of therapeutic genes. We synthesized bivalent molecules that link ligands of the transcription factor B cell lymphoma 6 (BCL6) to inhibitors of cyclin-dependent kinases (CDKs). These molecules relocalized CDK9 to BCL6-bound DNA and directed phosphorylation of RNA polymerase II. The resulting expression of pro-apoptotic, BCL6-target genes caused killing of diffuse large B cell lymphoma cells and specific ablation of the BCL6-regulated germinal center response. Genomics and proteomics corroborated a gain-of-function mechanism in which global kinase activity was not inhibited but rather redirected. Thus, kinase inhibitors can be used to context-specifically activate transcription."

A new technique signals cancer cells to self-destruct | Stanford Report "By switching on a natural process that triggers cell death, researchers hope to trick cancer cells into disposing of themselves."

Relocalizing transcriptional kinases to activate apoptosis

Turning kinase inhibitors into activators of therapeutic genes.