Fibrolamellar carcinoma (FLC) is a rare, aggressive liver cancer affecting adolescents and young adults. Nearly all cases contain the same genetic abnormality — a fusion protein called DNAJ‑PKAc. This study provides clear evidence that the fusion protein fundamentally reshapes both the metabolism of the cancer and immune behavior. Importantly, this rewiring reveals a specific therapeutic vulnerability that could be targeted with glutamine‑blocking drugs.
Key results and findings from the study:
- A new CRISPR‑engineered mouse model was developed. The researchers described a first-of-its-kind mouse model that expresses the DNAJ‑PKAc fusion while maintaining an intact immune system. This new mouse model, used in the research, provides a powerful platform for preclinical therapeutic development.
- The fusion protein rewires tumor metabolism. In both mouse models and human tumor samples, FLC cells consumed glutamine at extremely high rates and converted it into glutamate and ammonia. This explains why many FLC patients develop hyperammonemia. The DNAJ‑PKAc fusion forces FLC cells into a hyper‑metabolic state characterized by:
- A strong dependence on glutamine (“glutamine addiction”)
- Increased glycolysis (more glucose use and acid production)
- Enhanced nucleotide production to support rapid growth of the cancer
- Dysfunctional mitochondria that appear swollen and structurally abnormal.
- This metabolism suppresses the immune system, which can help explain FLC’s historically poor response to immunotherapy. The altered metabolism depletes nutrients that patients’ immune cells rely on and creates a environment around the tumor enriched with acidic substances and ammonia. This toxic environment:
- Reduces the ability of immune cells (CD8 cells) to infiltrate the tumor
- Weakens T‑cell activation
- Produces a broadly immunosuppressive tumor.
- Glutamine antagonists can reverse the fusion protein’s effects. The study tested an experimental glutamine‑blocking drug (JHU‑083) in the engineered mice which suggested that metabolism‑targeting therapy can potentially improve the effectiveness of immunotherapy in FLC. After treating the engineered mice with the drug:
- Tumor metabolism shifted back toward normal
- T cells regained activation and the ability to kill cancer cells
- Tumors shrank significantly, with the fusion-positive tumors being much more sensitive to the glutamine blockade than fusion‑negative ones.
- Combination therapy showed synergy. When JHU‑083 was combined with immune checkpoint inhibitors (anti‑PD‑1 and anti‑CTLA‑4):
- Tumor control improved dramatically
- Long‑term survival of the mice increased.
Bottom Line
For many years it has been known that DNAJ‑PKAc is the engine that drives fibrolamellar carcinoma. This study has demonstrated that one of its impacts is rewiring the cancer’s metabolism in a way that suppresses the immune system. Importantly, this rewiring may make the cancer vulnerable to drugs that block glutamine metabolism.
Based on these findings, a clinical trial is now underway at Johns Hopkins University in Baltimore, Maryland that is testing the effectiveness of a glutamine‑blocking therapy (DRP‑104) in combination with immunotherapy in FLC patients.
The full text of the article can be read here.
Note: This study was partially funded by a grant from FCF.