Authors
Soon Woo Nam
Published in
Critical reviews in oncology/hematology. Pages 105508. Jul 31, 2026. Epub Jul 31, 2026.
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer death, yet immune checkpoint inhibitors (ICIs) benefit only a minority of patients-a limitation attributed to low tumor mutational burden (TMB) and an immunologically cold microenvironment. SMG1, a serine/threonine kinase of the phosphatidylinositol 3-kinase-related kinase (PIKK) superfamily, sits at the intersection of RNA surveillance, the DNA damage response, and oncogenic signaling. As the master kinase of nonsense-mediated mRNA decay (NMD), SMG1 phosphorylates UPF1 to degrade transcripts bearing premature termination codons; independently, it restrains tumor growth by phosphorylating p53 (Ser15) and promoting Cdc25A turnover. SMG1 was originally identified as a tumor-suppressive modulator of sorafenib resistance in HCC (Nam, S.W. et al., 2014), and subsequent work shows SMG1 is reduced in HCC, predicts adverse outcome, and is recurrently silenced by reversible promoter hypermethylation. Paradoxically, the same kinase conceals mutation-derived neoantigens, and its selective inhibition (e.g., KVS0001) raises HLA class I neoantigen presentation toward high-TMB levels and improves checkpoint-inhibitor efficacy in preclinical and liver-specific models. This critical review integrates SMG1 structural biology, clinicopathology, signaling, sorafenib resistance, and NMD-directed immunotherapy, grading established versus inferential mechanisms, and nominates SMG1 and NMD as dual, context-dependent targets for HCC precision oncology.
PMID:
42537828
Bibliographic data and abstract were imported from PubMed on 01 Aug 2026.
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