Suppression of stress granule formation is a vulnerability imposed by mutant p53

Elizabeth Thoenen, Atul Ranjan, Alejandro Parrales, Shigeto Nishikawa, Dan A. Dixon, Sugako Oka and Tomoo Iwakuma ()
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Elizabeth Thoenen: Children’s Mercy Research Institute
Atul Ranjan: Children’s Mercy Research Institute
Alejandro Parrales: Children’s Mercy Research Institute
Shigeto Nishikawa: Children’s Mercy Research Institute
Dan A. Dixon: University of Arkansas for Medical Sciences
Sugako Oka: Kyushu University
Tomoo Iwakuma: Children’s Mercy Research Institute

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Missense mutations in the TP53 (p53) gene have been linked to malignant progression. However, our in-silico analyses reveal that hepatocellular carcinoma (HCC) patients with mutant p53 (mutp53) have better overall survival compared to those with p53-null (p53null) HCC, unlike other cancer types. Given the historical use of sorafenib (SOR) monotherapy for advanced HCC, we hypothesize that mutp53 increases sensitivity to SOR, a multikinase inhibitor that induces endoplasmic reticulum (ER) stress. Here we show that mutp53 inhibits stress granule (SG) formation by binding to an ER stress sensor, PKR-like ER kinase (PERK), and a key SG component, GAP SH3 domain-binding protein 1 (G3BP1), contributing to increased sensitivity of SG-competent cells and xenografts to ER stress inducers including SOR. Our study identifies a unique vulnerability imposed by mutp53, suggesting mutp53 as a biomarker for ER stress-inducing agents and highlighting the importance of SG inhibition for cancer treatment.

Date: 2025
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DOI: 10.1038/s41467-025-57539-6

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