| There's a decent amount of cynicism in the comments, which I understand. I think this is a really cool and novel study, though. Historically, cancer was treated with therapies that are toxic to all cells, relying on the fact that cancer cells divide quickly and are unable to handle stress as well as normal cells (chemotherapy, radiation). The last couple of decades we've seen many targeted cancer therapies. These drugs generally inhibit the activity of a specific protein that lets the cancer cells grow (e.g. EGFR inhibitors) or prevents the immune system from killing the cancer cells (e.g. PDL1 inhibitors). This mechanism is way more interesting. The gene BCL6 is usually turned on in immune cells when they are mutating to recognize foreign invaders. This process involves lots of DNA damage and stress, but BCL6 stops the cells from dying and is therefore important for normal immune function. Unfortunately, this makes BCL6 a gene that is often co-opted in cancer cells to help them survive. The method cleverly exploits the oncogenic function of BCL6 not by inhibiting it, but by turning it into a guide, enabling the delivery of activating machinery to the targets of BCL6 and reversing the inhibitory effects on cell death. The whole field of targeted degraders, molecular glues, and heterobifunctional molecules is a growing area of interest in cancer research. |
With "induced proximity" approaches like the one in this study, all you need is a molecule that binds the target protein somewhere. This idea has been validated extensively in the field of "targeted protein degradation", where a target protein and an E3 ubiquitin ligase, a protein that recruits the cell's native proteolysis machinery, are recruited to each other. The target protein doesn't have to be inactivated by the therapeutic molecule because the proteolysis machinery destroys it, so requirement #3 from above is effectively removed.
The molecule in this study does something similar to targeted protein degradation, but this time using a protein that effects gene expression instead of one that recruits proteolysis machinery. The article focuses on the fact that cancers are addicted to BCL6. This is an important innovation in the study and an active area of research (another example at [1]), but leaves out the fact that these induced proximity platforms are much more generalizable than traditional small molecules because it's the proteins that they recruit that do all the work rather than the molecules themselves. This study goes a long way to validate this principle, pioneered by targeted protein degradation and PROTACs, and shows that it can be applied broadly.
[1] https://www.biorxiv.org/content/10.1101/2024.07.27.605429v1