# The Fanconi Anemia Pathway Inhibits mTOR Signaling and Prevents Accelerated Translation in Head and Neck Cancer Cells

## TL;DR

This study shows that a faulty Fanconi anemia pathway in head and neck cancer cells boosts mTOR signaling, increasing protein production, and suggests mTOR inhibitors like rapamycin could be an effective treatment.

## Contribution

The study reveals a novel role of the Fanconi anemia pathway in suppressing mTOR signaling and identifies mTOR inhibition as a potential therapeutic strategy for FA− head and neck cancers.

## Key findings

- FA− cells show elevated amino acids, protein content, and translation due to mTOR hyperactivation.
- Rapamycin reduces mTOR activity and translation in FA− cells but not in FA+ cells.
- FA− cells are more sensitive to rapamycin under nutrient stress, indicating a therapeutic vulnerability.

## Abstract

The Fanconi anemia (FA) pathway is essential for DNA repair and maintenance of genome integrity. Individuals born without a functional FA pathway are at high risk of developing head and neck cancer early in life, often with poor prognosis. We sought to define whether a nonfunctional FA pathway affects cellular metabolism and related signal transduction. FA loss stimulated amino acid accumulation, translation, and protein production via mTOR signaling, which is reported to promote cancer development and progression. Pharmacological mTOR inhibition using rapamycin suppressed these pro-cancer phenotypes, suggesting that targeting protein synthesis may offer a therapeutic avenue for the management of FA− associated cancers.

Background/Objectives: The Fanconi anemia (FA) pathway is essential for the repair of DNA interstrand crosslinks and maintenance of genomic stability. Germline loss of FA pathway function in the inherited Fanconi anemia syndrome leads to increased DNA damage and a range of clinical phenotypes, including a heightened risk of head and neck squamous cell carcinoma (HNSCC). Non-synonymous FA gene mutations are also observed in up to 20% of sporadic HNSCCs. The mechanistic target of rapamycin (mTOR) is known to stimulate cell growth, anabolic metabolism including protein synthesis, and survival following genotoxic stress. Methods/Results: Here, we demonstrate that FA− deficient (FA−) HNSCC cells exhibit elevated intracellular amino acid levels, increased total protein content, and an increase in protein synthesis indicative of enhanced translation. These changes are accompanied by hyperactivation of the mTOR effectors translation initiation factor 4E Binding Protein 1 (4E-BP1) and ribosomal protein S6. Treatment with the mTOR inhibitor rapamycin reduced the phosphorylation of these targets and blocked translation specifically in FA− cells but not in their isogenic FA− proficient (FA+) counterparts. Rapamycin-mediated mTOR inhibition sensitized FA− but not FA+ cells to rapamycin under nutrient stress, supporting a therapeutic metabolism-based vulnerability in FA− cancer cells. Conclusions: These findings uncover a novel role for the FA pathway in suppressing mTOR signaling and identify mTOR inhibition as a potential strategy for targeting FA− HNSCCs.