January, 2023

Oncogenic Addiction of Fibrolamellar Hepatocellular Carcinoma to the Fusion Kinase DNAJB1-PRKACA 

Clinical Cancer Research

Hepatocellular fibrolamellar carcinoma (FLC) is caused by an abnormal protein. Called DNAJB1-PRKACA, or chimera for short, it causes the tumor to arise when liver cells make it. Chimera is made in liver cells as the result of a rare and seemingly random DNA mutation. If there were some way to eliminate it from tumor cells, the cancer might go away. But that hope is based on an important assumption. For chimera to be a good target for therapy, it must not only cause FLC but also continue to act to keep tumor cells alive and growing. That is true for some mutations that cause cancer, but not all. In some cancers an initiating mutation triggers later events, and then is no longer needed by the tumor. What about in FLC? This paper by Neumayer and colleagues answers the question for the first time, and the answer is yes- removing the chimera from FLC tumor cells causes them to die. This was shown using tumor cells taken from FLC patients and grown in the laboratory in dishes with a nutrient solution. To stop the cells from making chimera, a chemical was introduced called short hairpin RNA (shRNA). The shRNA was a very specific sort, one that exactly matches the structure of a portion of chimera messenger RNA. Chimera messenger RNA delivers the information (from mutant DNA) that directs cells to make chimera protein. The shRNA used in these experiments prevents chimera messenger RNA from delivering that message, and thus cuts off the supply of chimera protein. FLC cells in a dish died when that was. This also worked in a living experimental animal. When FLC cells are put in mice, they divide and form tumors.  Turning off the supply of chimera messenger RNA in these growing tumors caused them to shrink dramatically. These results support an important, novel and encouraging conclusion: taking away chimera protein from FLC cells does more than slow them down: it kills them. FLC is addicted to chimera, and cannot live without it. Strategies targeting the chimera make good sense, but this is only one step toward curing FLC. Ways must be found to stop chimera in most or even all FLC cells of a patient. Methods to do that are under development.

Written by Dr. Phil Coffino