Shirani, M.; Bowie, R. S.; Tomasini, M.; Hook, R.; Ng, D.; Shebl, B.; Lyons, B.; Coffino, P.; Simon, S. M.

Oncogenic fusions of two native proteins are challenging to block without disturbing the parental proteins. A mRNA delivered peptide degrader, selectively eliminates the oncogenic fusions DNAJB1::PRKACA and ATP1B1::PRKACA in fibrolamellar carcinoma (FLC), cholangiocarcinoma and intraductal pancreatic neoplasm, without effect on native PRKACA. Specific degradation reflected structural properties of the fusion proteins. The degrader was lethal to FLC tumor cells in a preclinical model, with no effect on non-FLC cells. To enhance efficacy and speed, we modified the mRNA to simultaneously encode the degrader and an siRNA against the fusion transcript, reducing new protein synthesis which accelerated degradation of DNAJB1::PRKACA, offering a wide therapeutic index for mutation-driven disease.