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

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• FOXO1 gene fusions are key drivers in a subset of rhabdomyosarcoma (RMS), a pediatric cancer with poor survival rates.
• Current therapies are ineffective against these fusion-driven cancers, necessitating the identification of novel therapeutic targets.

Purpose of the Study:

• To identify genetic dependencies specific to PAX3-FOXO1-driven RMS using a CRISPR-interference screen.
• To explore the therapeutic potential of targeting identified vulnerabilities in FOXO1-fusion-positive RMS.

Main Methods:

• Conducted an isogenic CRISPR-interference screen to identify PAX3-FOXO1-specific genetic dependencies.
• Investigated the role of the GATOR2 complex in regulating mTORC1 signaling and cell cycle progression.
• Utilized in vivo tumor xenograft models to assess the therapeutic efficacy of targeting GATOR2 and mTORC1.

Main Results:

• Identified the GATOR2 complex as a critical dependency in PAX3-FOXO1-driven RMS.
• Demonstrated that GATOR2 loss abrogates amino acid-induced mTORC1 signaling, impeding cell cycle progression.
• Showcased that targeting GATOR2 or using an mTORC1 inhibitor induced tumor regressions in preclinical models.

Conclusions:

• Loss of GATOR2 function represents a significant vulnerability in FOXO1 fusion-positive RMS.
• Targeting the GATOR2 complex or utilizing mTORC1 inhibitors presents a promising therapeutic strategy for this intractable pediatric cancer.
• Isogenic genetic screens are valuable for uncovering druggable vulnerabilities in fusion-driven pediatric cancers.