| Autor: |
Jacqueline Morales, David V. Allegakoen, José A. Garcia, Kristen Kwong, Pushpendra K. Sahu, Drew A. Fajardo, Yue Pan, Max A. Horlbeck, Jonathan S. Weissman, W. Clay Gustafson, Trever G. Bivona, Amit J. Sabnis |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
|
| Zdroj: |
JCI Insight, Vol 7, Iss 23 (2022) |
| Druh dokumentu: |
article |
| ISSN: |
2379-3708 |
| DOI: |
10.1172/jci.insight.162207 |
| Popis: |
Oncogenic FOXO1 gene fusions drive a subset of rhabdomyosarcoma (RMS) with poor survival; to date, these cancer drivers are therapeutically intractable. To identify new therapies for this disease, we undertook an isogenic CRISPR-interference screen to define PAX3-FOXO1–specific genetic dependencies and identified genes in the GATOR2 complex. GATOR2 loss in RMS abrogated aa-induced lysosomal localization of mTORC1 and consequent downstream signaling, slowing G1-S cell cycle transition. In vivo suppression of GATOR2 impaired the growth of tumor xenografts and favored the outgrowth of cells lacking PAX3-FOXO1. Loss of a subset of GATOR2 members can be compensated by direct genetic activation of mTORC1. RAS mutations are also sufficient to decouple mTORC1 activation from GATOR2, and indeed, fusion-negative RMS harboring such mutations exhibit aa-independent mTORC1 activity. A bisteric, mTORC1-selective small molecule induced tumor regressions in fusion-positive patient-derived tumor xenografts. These findings highlight a vulnerability in FOXO1 fusion–positive RMS and provide rationale for the clinical evaluation of bisteric mTORC1 inhibitors, currently in phase I testing, to treat this disease. Isogenic genetic screens can, thus, identify potentially exploitable vulnerabilities in fusion-driven pediatric cancers that otherwise remain mostly undruggable. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
|
