Fibrolamellar carcinoma (FLC) is a rare, aggressive liver cancer primarily affecting young individuals, with limited treatment options and poor prognosis. The discovery of the DNAJB1-PRKACA gene fusion as the primary oncogenic driver in FLC over a decade ago has reshaped research efforts. The exact way the DNAJ-PKAc protein causes cancer is still unclear, but research shows it changes the cell’s epigenetic structure and creates super-enhancers—special DNA regions that turn on important cancer genes. These super-enhancers make certain genes, like SLC16A14 and LINC00473, highly active in fibrolamellar carcinoma (FLC). These genes are unique to FLC and could potentially act as markers of the disease.
RNA polymerase II, an enzyme that helps make RNA, is very active at these super-enhancers. In FLC samples, the Ronnekliev-Kelly team determined that RNA polymerase II showed increased phosphorylation at a specific site called Serine-5 (Ser 5), which is controlled by another protein called CDK7. This suggests that CDK7 might play a key role in driving the abnormal gene activity in FLC and could potentially be an attractive therapeutic target.
Consequently, the study team investigated the role of CDK7, a serine/threonine kinase that has attracted attention in cancer research because it regulates both the cell cycle and gene transcription. While CDK7 has been studied in cancers such as breast, prostate, and lung, this study is the first to examine its role in fibrolamellar carcinoma (FLC). Key findings of the published study include:
- Both FLC tumors and engineered cell models exhibit heightened CDK7 activity and increased RNA Pol II Ser5 phosphorylation.
- When scientists blocked CDK7 using investigational new drugs (including SY-5609 and YKL-5-124), cancer cells died, but normal liver cells were fine—identifying a possible new treatment option for the disease.
- Combination therapy including CDK7 and CDK9 inhibitors (including the investigational drugs, VIP-152, NVP-2) also shows synergistic effects, stopping FLC-specific gene expression and killing cells more effectively.
Key implications of the study
Based on this study, the team concluded that:
- CDK7 plays a key role in controlling gene activity in FLC
- Inhibition of CDK7 offers a promising new target for drug development for the disease.
- Dual inhibition of CDK7 and CDK9 may offer a promising therapeutic strategy for FLC, warranting further investigation.
The full text of the publication can be accessed here.