ASO-based PKM splice-switching therapy inhibits hepatocellular carcinoma growth.

Ma, Wai Kit, Voss, Dillon M, Scharner, Juergen, Costa, Ana SH, Lin, Kuang-Ting, Jeon, Hyun Yong, Wilkinson, John E, Jackson, Michaela, Rigo, Frank, Bennett, C Frank, Krainer, Adrian R (December 2021) ASO-based PKM splice-switching therapy inhibits hepatocellular carcinoma growth. Cancer Research. canres.0948.2020-canres.0948.2020. ISSN 0008-5472

DOI: 10.1158/0008-5472.CAN-20-0948


The M2 pyruvate kinase (PKM2) isoform is upregulated in most cancers and plays a crucial role in regulation of the Warburg effect, which is characterized by the preference for aerobic glycolysis over oxidative phosphorylation for energy metabolism. PKM2 is an alternative-splice isoform of the PKM gene and is a potential therapeutic target. Antisense oligonucleotides (ASO) that switch PKM splicing from the cancer-associated PKM2 to the PKM1 isoform have been shown to induce apoptosis in cultured glioblastoma cells when delivered by lipofection. Here, we explore the potential of ASO-based PKM splice switching as a targeted therapy for liver cancer. A more potent lead cEt/DNA ASO induced PKM splice-switching and inhibited the growth of cultured hepatocellular carcinoma (HCC) cells. This PKM isoform switch increased pyruvate-kinase activity and altered glucose metabolism. In an orthotopic HCC xenograft mouse model, the lead ASO and a second ASO targeting a non-overlapping site inhibited tumor growth. Finally, in a genetic HCC mouse model, a surrogate mouse-specific ASO induced Pkm splice switching and inhibited tumorigenesis, without observable toxicity. These results lay the groundwork for a potential ASO-based splicing therapy for HCC.

Item Type: Paper
Subjects: diseases & disorders > cancer > cancer types > liver cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > RNA splicing
diseases & disorders > viral diseases > coronavirus > therapies and treatments
CSHL Authors:
Communities: CSHL labs > Krainer lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 17 December 2021
Date Deposited: 22 Dec 2021 15:53
Last Modified: 08 Mar 2022 15:54
PMCID: PMC8898261

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