A new study, recently published in eLife by Dr. John Gordan of UCSF, elaborates some of the downstream effects of protein kinase A (PKA) in certain cancers, including fibrolamellar. Genetic alterations that activate PKA are found in many cancer types (such as the DNAJB1-PRKACA fusion in FLC), but how that signalling leads to cancer formation is poorly understood. Because PKA signaling is essential for survival, direct inhibition of the FLC fusion has not yet been demonstrated without creating intolerable side effects. By understanding the downstream effects of PKA that cause growth of tumors, researchers hope to identify other potential targets for therapeutic development.
In work funded by FCF, Gordan’s team has developed a detailed understanding of certain signaling pathways that are activated by DNAJ-PKAc. The study reports that common downstream effects of the fusion include increased c-MYC protein expression. MYC is an oncogene involved in cell proliferation, and it appears that FLC is dependent on MYC for growth. Second, the team found that the fusion increases MYC levels by signaling to eIF-4A (eukaryotic Initiation Factor 4A), an enzyme involved in protein translation. The team also found that a FLC cell line is highly sensitive to zotatifin, an eIF-4A inhibitor currently in Phase 1 clinical trials.
For FLC, the study identifies zotatifin as a drug candidate requiring further study. Additional in vivo validation in multiple models will be necessary to confirm its relevance to the cancer. With more study, it may be possible to show that targeting MYC by inhibiting its translation could eventually lead to new treatment options for patients with FLC.
Click here to read or download the complete study.