Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Nat Commun. 2022 Jun 8;13(1):3181. doi: 10.1038/s41467-022-30794-7.
The RNF43_p.G659fs mutation occurs frequently in colorectal cancer, but its function remains poorly understood and there are no specific therapies directed against this alteration. In this study, we find that RNF43_p.G659fs promotes cell growth independent of Wnt signaling. We perform a drug repurposing library screen and discover that cells with RNF43_p.G659 mutations are selectively killed by inhibition of PI3K signaling. PI3K/mTOR inhibitors yield promising antitumor activity in RNF43 isogenic cell lines and xenograft models, as well as in patient-derived organoids harboring RNF43_p.G659fs mutations. We find that RNF43 binds p85 leading to increased PI3K signaling through p85 ubiquitination and degradation. Additionally, RNA-sequencing of RNF43 isogenic cells reveals decreased interferon response gene expression, that is reversed by PI3K/mTOR inhibition, suggesting that RNF43 may alter tumor immunity. Our findings suggest a therapeutic application for PI3K/mTOR inhibitors in treating RNF43_p.G659fs mutant cancers.
RNF43_p.G659fs 突变在结直肠癌中经常发生，但它的功能仍不清楚，也没有针对这种改变的特定治疗方法。在这项研究中，我们发现 RNF43_p.G659fs 促进了细胞生长，而不依赖于 Wnt 信号。我们进行了药物再利用文库筛选，发现具有 RNF43_p.G659 突变的细胞可以被抑制 PI3K 信号选择性杀死。PI3K/mTOR 抑制剂在 RNF43 同基因细胞系和异种移植模型中以及携带 RNF43_p.G659fs 突变的患者来源类器官中显示出有前景的抗肿瘤活性。我们发现 RNF43 与 p85 结合，导致 PI3K 信号通过 p85 泛素化和降解增加。此外，RNF43 同基因细胞的 RNA 测序显示干扰素反应基因表达减少，这可被 PI3K/mTOR 抑制逆转，提示 RNF43 可能改变肿瘤免疫。我们的研究结果表明，PI3K/mTOR 抑制剂在治疗 RNF43_p.G659fs 突变型癌症方面具有治疗应用。
