Fibrolamellar carcinoma (FLC) is driven by a unique fusion protein called DNAJB1::PRKACA (DP). This fusion is responsible for the growth of the tumor cells, and without it, the tumor dies. Unfortunately, targeting this fusion with drugs has proven extremely difficult, because the fusion’s active site is almost identical to that of normal protein kinase A (PKA), a protein essential to healthy cells.
This study outlines a potential new approach to developing a drug against DP — combining a degrader that forces cancer cells to destroy the fusion protein with an additional compound (a small interfering RNA) that interferes with new production of fusion proteins.
Key findings of the study:
- A new degrader can selectively destroy the FLC fusion protein. In the study, the team engineered a degrader by attaching a small part of a natural PKA‑inhibitor protein (PKI) to an E3 ligase called SPOP. This degrader binds to the fusion protein and sends it to the cell’s waste‑disposal machinery (the proteasome) for destruction. The team cleverly designed this degrader from a non-selective molecule, taking advantage of DP’s longer, flexible structure and the fact that it accumulates in a cell’s nucleus, while normal PKA stays mostly in the cytoplasm. As a result, the degrader (PKI-SPOP) can selectively eliminate the fusion protein without impacting normal PKA.
- The degrader can stop FLC tumor growth. In both cell cultures and mouse models (including patient‑derived xenografts), the degrader stopped FLC tumor growth while showing no detectable toxicity to healthy liver cells. Tested mice maintained normal weight and liver chemistries, indicating the approach could have a wide therapeutic safety margin.
- The degrader can be delivered as mRNA. Instead of delivering the degrader as a protein, researchers encoded it in mRNA, similar to a mRNA vaccine. Messenger ribonucleic acid (mRNA) is a molecule that copies instructions from a cell’s DNA and brings them to ribosomes (a cell’s protein-making structures). The ribosomes use the instructions on mRNA to manufacture encoded proteins. This approach allows rapid redesign of the degrader, and the incorporation of components that could be difficult to deliver via a different drug delivery approach.
- A combination of the degrader and siRNA therapy is more effective. The team created a single mRNA molecule that encodes both the degrader and a siRNA to block new fusion protein production. This combined approach should reduce fusion protein to lower levels and could make resistance to the therapy less likely.
Implications:
This work establishes a new therapeutic approach that selectively targets the FLC fusion protein while sparing the normal protein. However, additional work remains for this approach to become a patient treatment, since efficiently targeting an mRNA-encoded degrader to tumor cells can be challenging.
The full pre-print of this article can be accessed here.