Timeframe: 2017 – 2018
Goal: Characterize inhibition of the DnaJ-PKAc chimeric protein in fibrolamellar carcinoma
Principal Investigator: Hibba tul Rehman, MD
Study overview: The DNAJB1-PRKACA fusion gene produces the DNAJ-PKAc fusion kinase protein, which is present in nearly all FLC tumors and promotes liver tumor formation in mice. Kinases, including fusion kinases, have been successful drug targets in numerous cancer types. Inhibition of DnaJ-PKAc may provide a targeted therapy for FLC. This study proposed a two pronged approach towards identifying therapeutic inhibitors of the fusion:
- Screening a previously developed peptide library to identify peptides that preferentially bind chimeric DnaJ-PKAc over normal, wide-type protein in vitro.
- Developing a library of inhibitory peptides that would preferentially inhibit DnaJ-PKAc.
The aim of these efforts was to develop an understanding that will support the development of inhibitors that regulate the function of the chimeric kinase without affecting the wild-type kinase, thus selectively targeting cancer cells without affecting healthy tissue.
Key Findings: The study analyzed a library of small inhibitor peptides derived from endogenous PKI (which inhibit wild-type PKA in the body), which showed no preferential competitive inhibition of wild-type PKA versus DnaJ-PKAc. This result was due to the overwhelming structural similarities observed at the active sites of wtPKA and DnaJ-PKAc. A survey of publicly-available data sets to determine the predominant isoform(s) of PKI expressed in normal liver and FLC tumors showed that PKIβ was likely to be the predominant isoform expressed in human liver. Upon testing of the inhibitory properties of full-length PKIβ, identical inhibition of both wtPKAc and DnaJ-PKAc was observed.
Details of the analysis was published in April 2019 in The Journal of Cellular Biochemistry. The full article can be read or downloaded here.
Implications: This study showed the importance of adopting a targeted approach to inhibiting DNAJ-PKAc in FLC.