GATOR2-dependent mTORC1 activity is a therapeutic vulnerability in FOXO1 fusion–positive rhabdomyosarcoma
Name
162207.2-20221121124646-covered-4fa089109ce452e764bbb8648b44a723.pdf
Description
Published version
Size
7.04 MB
Format
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Checksum (MD5)
dd10dc36759f1af64ab0bff04b525ac5
Author(s)
Morales, Jacqueline
Allegakoen, David V
Garcia, José A
Kwong, Kristen
Sahu, Pushpendra K
Fajardo, Drew A
Pan, Yue
Horlbeck, Max A
Weissman, Jonathan S
Gustafson, W Clay
Date Issued
October 25, 2022
Journal
JCI Insight
Publisher
American Society for Clinical Investigation
Version
Final published version
Abstract
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.
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DOI of Published Version
https://doi.org/10.1172/jci.insight.162207
