GATOR2-Dependent mTORC1 Activity is a Therapeutic Vulnerability in FOXO1 Fusion-Positive Rhabdomyosarcoma

Authors

Jacqueline Morales, University of California, San Francisco
David V. Allegakoen, University of California, San Francisco
José A. Garcia, Kansas City University
Kristen Kwong, University of California, San Francisco
Pushpendra K. Sahu, University of California, San Francisco
Drew A. Fajardo, University of California, San Francisco
Yue Pan, University of California, San Francisco
Max A. Horlbeck, University of California, San Francisco
Jonathan S. Weissman, University of California, San Francisco
W. Clay Gustafson, Revolution Medicines
Trever G. Bivona, University of California, San Francisco
Amit J. Sabnis, University of California, San Francisco

Document Type

Article

Publication Title

JCI Insight

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.

DOI

10.1172/jci.insight.162207

Publication Date

12-8-2022

Keywords

Cancer, Drug therapy, Genetics, Oncology, Signal transduction

ISSN

2379-3708

Recommended Citation

Morales J, Allegakoen DV, Garcia JA, Kwong K, Sahu PK, Fajardo DA, Pan Y, Horlbeck MA, Weissman JS, Gustafson W, Bivona TG, Sabnis AJ. GATOR2-Dependent mTORC1 Activity is a Therapeutic Vulnerability in FOXO1 Fusion-Positive Rhabdomyosarcoma. JCI Insight. 2022; 7(23). doi: 10.1172/jci.insight.162207.