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TFE3 fusions direct an oncogenic transcriptional program that drives OXPHOS and unveils vulnerabilities in

Jiao Li1,2, Kaimeng Huang2,3, Fiona McBride1

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute; Boston, MA, USA.

Biorxiv : the Preprint Server for Biology
|August 16, 2024
PubMed

Insights

Translocation renal cell carcinoma (tRCC) driven by TFE3 fusions relies on oxidative phosphorylation (OXPHOS). Inhibiting EGLN1 exploits this metabolic vulnerability, offering a new therapeutic strategy for tRCC.

Area of Science:

  • Oncology
  • Metabolic pathways
  • Cancer genetics

Background:

  • Translocation renal cell carcinoma (tRCC) is an aggressive kidney cancer subtype.
  • The downstream mechanisms of TFE3 gene fusions driving tRCC are poorly understood.

Purpose of the Study:

  • To investigate the metabolic rewiring in tRCC driven by TFE3 fusions.
  • To identify tRCC-specific vulnerabilities associated with its metabolic state.
  • To explore EGLN1 inhibition as a potential therapeutic strategy.

Main Methods:

  • Transcriptional analysis of TFE3-fusion-driven metabolic pathways.
  • Genome-scale CRISPR screening to identify tRCC-selective vulnerabilities.
  • Assessment of EGLN1 inhibition effects on tRCC cell growth and metabolism.

Main Results:

  • TFE3 fusions promote oxidative phosphorylation (OXPHOS) in tRCC, unlike other renal cancers.
  • tRCCs exhibit heightened glutathione levels, leading to sensitivity to reductive stress.
  • Genome-scale CRISPR screening identified EGLN1 as a tRCC-selective vulnerability.
  • EGLN1 inhibition stabilizes HIF-1α, represses OXPHOS, and inhibits tRCC growth.

Conclusions:

  • TFE3 fusions establish a unique OXPHOS-dependent metabolic program in tRCC.
  • EGLN1 inhibition represents a promising therapeutic strategy for tRCC by targeting its metabolic rewiring.

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