It has long been known that almost all cases of FLC are caused by a unique abnormal protein called DNAJ‑PKAc, but scientists haven’t fully understood how it drives cancer growth. Consequently, the researchers set out to understand how this abnormal protein helps cancer cells grow and identify weak points in the cancer that could be targeted with drugs.
To do that, the team used a combination of:
- Lab-grown cancer cells
- Patient-derived tumor samples
- Mouse models of FLC
- A large-scale screening method to test many cancer-related enzymes (called kinases).
In the study, the team found that FLC cancer cells depend heavily on a protein called PLK1, which controls cell division. When PLK1 was blocked or removed, cancer cells grew much more slowly and often died. The investigators determined that this happens because the cancer-causing fusion protein activates PLK1. It does this at a specific location inside cells called the centrosome, which helps organize cell division.
When researchers tested drugs that inhibit PLK1, they found that FLC cells were much more sensitive to the drug than normal liver cells, and relatively low doses were able to slow or stop tumor growth. These PLK1 inhibitors:
- Reduced tumor growth in mice implanted with human FLC tumors
- Improved survival rates in animal studies
- Reduced tumor activity in real human tumor samples tested in the lab.
In addition, the combination of a PLK1 inhibitor with a chemotherapy drug (irinotecan) completely stopped tumor growth in a mouse model of liver tumors.
Key implications of the effort
This study shows:
- The DNAJ‑PKAc mutation rewires cancer cells so they become more dependent on PLK1
- That dependency creates a potential target for treatment.
Most importantly, several drugs that block PLK1 are already in clinical development. This opens a new promising path toward new treatments for FLC patients.
Note: This study was partially funded by a grant from FCF