| First Author | Loe AKH | Year | 2021 |
| Journal | J Exp Med | Volume | 218 |
| Issue | 6 | PubMed ID | 33822841 |
| Mgi Jnum | J:307805 | Mgi Id | MGI:6724830 |
| Doi | 10.1084/jem.20200219 | Citation | Loe AKH, et al. (2021) Uncovering the dosage-dependent roles of Arid1a in gastric tumorigenesis for combinatorial drug therapy. J Exp Med 218(6) |
| abstractText | Gastric cancer (GC) is one of the most common deadly cancers in the world. Although patient genomic data have identified AT-rich interaction domain 1A (ARID1A), a key chromatin remodeling complex subunit, as the second most frequently mutated gene after TP53, its in vivo role and relationship to TP53 in gastric tumorigenesis remains unclear. Establishing a novel mouse model that reflects the ARID1A heterozygous mutations found in the majority of human GC cases, we demonstrated that Arid1a heterozygosity facilitates tumor progression through a global loss of enhancers and subsequent suppression of the p53 and apoptosis pathways. Moreover, mouse genetic and single-cell analyses demonstrated that the homozygous deletion of Arid1a confers a competitive disadvantage through the activation of the p53 pathway, highlighting its distinct dosage-dependent roles. Using this unique vulnerability of Arid1a mutated GC cells, our combined treatment with the epigenetic inhibitor, TP064, and the p53 agonist, Nutlin-3, inhibited growth of Arid1a heterozygous tumor organoids, providing a novel therapeutic option for GC. |
