GATOR2-dependent mTORC1 activity is a therapeutic vulnerability in FOXO1 fusion-positive rhabdomyosarcoma

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.

Automated summary

The study reveals that loss of GATOR2 complex impairs mTORC1 signaling and cell cycle transition in FOXO1 fusion-positive rhabdomyosarcoma (RMS). Suppression of GATOR2 inhibits tumor growth and favors the outgrowth of cells lacking PAX3-FOXO1. Genetic activation of mTORC1 can compensate for the loss of certain GATOR2 members. RAS mutations can decouple mTORC1 activation from GATOR2, resulting in aa-independent mTORC1 activity in fusion-negative RMS. A bisteric, mTORC1-selective small molecule induces tumor regressions in fusion-positive patient-derived tumor xenografts.