ASO-based PKM Splice-switching Therapy Inhibits Hepatocellular Carcinoma Cell Growth

Ma, W. K.; Scharner, J.; Costa, A. S. H.; Jeong, H. Y.; Jackson, M.; Rigo, F.; Bennett, F. C.; Krainer, A.

doi:10.1101/2020.09.01.278580

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bioRxiv · 10.1101/2020.09.01.278580

ASO-based PKM Splice-switching Therapy Inhibits Hepatocellular Carcinoma Cell Growth

Ma, W. K.·Scharner, J.·Costa, A. S. H.·Jeong, H. Y.·Jackson, M.·Rigo, F.·Bennett, F. C.·Krainer, A.

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Abstract

The M2 pyruvate kinase (PKM2) isoform is upregulated in most cancers and plays a crucial role in the Warburg effect, which is characterized by the preference for aerobic glycolysis for energy metabolism. PKM2 is an alternative-splice isoform of the PKM gene and is a potential therapeutic target. Previously, we developed antisense oligonucleotides (ASOs) that switch PKM splicing from the cancer-associated PKM2 to the PKM1 isoform and induce apoptosis in cultured glioblastoma cells. Here, we explore the potential of ASO-based PKM splice-switching as a targeted therapy for liver cancer. We utilize a more potent lead cEt/DNA ASO and demonstrate that it induces PKM splice-switching and inhibits the growth of cultured hepatocellular-carcinoma (HCC) cells. This PKM isoform switch increases pyruvate-kinase activity and alters glucose metabolism. The lead ASO and a second ASO targeting a non-overlapping site inhibit tumorigenesis in an orthotopic-xenograft HCC mouse model. Finally, a surrogate mouse-specific ASO induces Pkm splice-switching and inhibits HCC growth, without observable toxicity, in a genetic HCC mouse model. These results lay the groundwork for a potential ASO therapy for HCC. Statement of significanceAntisense oligonucleotides are used to force a change in PKM isoform usage in HCC, reversing the Warburg effect and inhibiting tumorigenesis.

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Ma, W. K., Scharner, J., Costa, A. S. H., Jeong, H. Y., Jackson, M., Rigo, F., Bennett, F. C., Krainer, A.. 2020-09-02. ASO-based PKM Splice-switching Therapy Inhibits Hepatocellular Carcinoma Cell Growth. https://doi.org/10.1101/2020.09.01.278580

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