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DNAJB1-PRKACA Fusion Drives Fibrolamellar Liver Cancer through Impaired SIK Signaling and CRTC2/p300-Mediated
Ilaria Gritti1,2,3,4, Jinkai Wan1,2,3,4, Vajira Weeresekara1,2,3,4
1Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts.
Cancer Discovery
|September 26, 2024
Summary
Researchers identified a key cancer-driving pathway in Fibrolamellar Hepatocellular Carcinoma (FLC) involving DNAJB1-PRKACA fusions. This fusion protein disrupts normal cell signaling, promoting tumor growth and offering new therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Fibrolamellar Hepatocellular Carcinoma (FLC) is a rare liver cancer.
- The specific molecular drivers of FLC remain incompletely understood.
- Identifying oncogenic pathways is crucial for targeted therapy development.
Purpose of the Study:
- To elucidate the central oncogenic pathway in FLC.
- To investigate the role of DNAJB1-PRKACA fusions in FLC pathogenesis.
- To identify potential therapeutic targets for FLC.
Main Methods:
- Functional studies in model systems.
- Examination of human FLC tumor specimens.
- Analysis of molecular signaling pathways, including protein interactions and transcriptional regulation.
Main Results:
- A novel oncogenic pathway driven by DNAJB1-PRKACA fusions was identified in FLC.
- The fusion protein mediates inactivation of SIK (Salt-inducible kinase).
- This inactivation stimulates CRTC2-p300-mediated transcription, promoting tumor growth.
Conclusions:
- DNAJB1-PRKACA fusions are central drivers of FLC.
- The identified pathway provides insight into FLC pathogenesis.
- This discovery informs the development of targeted therapies for FLC.
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