| First Author | Leibowitz BJ | Year | 2023 |
| Journal | Oncogene | Volume | 42 |
| Issue | 24 | Pages | 2007-2016 |
| PubMed ID | 37138032 | Mgi Jnum | J:337525 |
| Mgi Id | MGI:7494427 | Doi | 10.1038/s41388-023-02706-6 |
| Citation | Leibowitz BJ, et al. (2023) mTOR inhibition suppresses Myc-driven polyposis by inducing immunogenic cell death. Oncogene 42(24):2007-2016 |
| abstractText | Myc is a key driver of colorectal cancer initiation and progression, but remains a difficult drug target. In this study, we show that mTOR inhibition potently suppresses intestinal polyp formation, regresses established polyps, and prolongs lifespan of APC(Min/+) mice. Everolimus in diet strongly reduces p-4EBP1, p-S6, and Myc levels, and induces apoptosis of cells with activated beta-catenin (p-S552) in the polyps on day 3. The cell death is accompanied by ER stress, activation of the extrinsic apoptotic pathway, innate immune cell recruitment, and followed by T-cell infiltration on day 14 persisting for months thereafter. These effects are absent in normal intestinal crypts with physiologic levels of Myc and a high rate of proliferation. Using normal human colonic epithelial cells, EIF4E S209A knockin and BID knockout mice, we found that local inflammation and antitumor efficacy of Everolimus requires Myc-dependent induction of ER stress and apoptosis. These findings demonstrate mTOR and deregulated Myc as a selective vulnerability of mutant APC-driven intestinal tumorigenesis, whose inhibition disrupts metabolic and immune adaptation and reactivates immune surveillance necessary for long-term tumor control. |
