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  3. All-trans retinoic acid-mediated ADAR1 degradation synergizes with PD-1 blockade to suppress pancreatic cancer

All-trans retinoic acid-mediated ADAR1 degradation synergizes with PD-1 blockade to suppress pancreatic cancer

  • bioRxiv. 2024 Oct 23:2024.10.20.619300. doi: 10.1101/2024.10.20.619300.
Ching-Fei Li,  Li-Yuan Bai,  Yongkun Wei,  Heng-Huan Lee,  Riyao Yang,  Jun Yao,  Huamin Wang,  Ying-Nai Wang,  Wei-Chao Chang,  Yi-Chun Shen,  Shao-Chun Wang,  Cheng-Wei Chou,  Jie Fu,  Jianhua Ling,  Yu-Yi Chu,  Chang-Fang Chiu,  Michael Wang,  Dihua Yu,  Paul J Chiao,  Han Liang,  Anirban Maitra,  Haoqiang Ying,  Mien-Chie Hung
PMID: 39484589 DOI: 10.1101/2024.10.20.619300
Abstract

As a double-stranded RNA-editing Enzyme and an interferon-stimulated gene, double-stranded RNA-specific Adenosine Deaminase (ADAR1) suppresses interferon signaling and contributes to immunotherapy resistance. Suppression of ADAR1 overcomes immunotherapy resistance in preclinical models, but has not yet been translated to clinical settings. By conducting a screening of a subset of the FDA-approved drugs, we found that all-trans retinoic acid (ATRA, also known as tretinoin) caused ADAR1 protein degradation through ubiquitin-proteasome pathways and concomitantly increased PD-L1 expression in pancreatic and breast cancers. In addition, the combination of ATRA and PD-1 blockade reprogrammed the tumor microenvironment and unleashed antitumor immunity and thereby impeded tumor growth in pancreatic Cancer mouse models. In a pilot clinical trial, a higher dose of ATRA plus the anti-PD-1 antibody nivolumab prolonged median overall survival in patients with chemotherapy-resistant pancreatic Cancer compared to a lower dose of the same regimen. In this study, ATRA was the first drug to be found to cause ADAR1 degradation. We propose translation of a promising 2-pronged antitumor strategy using ATRA and nivolumab to convert immunologically "cold" into "hot" tumors susceptible to immune checkpoint blockade.

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