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4E-BP1 Is a Tumor Suppressor Protein Reactivated by mTOR Inhibition in Head and Neck Cancer
Zhiyong Wang1,2, Xiaodong Feng1, Alfredo A Molinolo1
1Moores Cancer Center, University of California, San Diego, La Jolla, California.
Abstract:
Aberrant activation of the PI3K-mTOR signaling pathway occurs in >80% of head and neck squamous cell carcinomas (HNSCC), and overreliance on this signaling circuit may in turn represent a cancer-specific vulnerability that can be exploited therapeutically. mTOR inhibitors (mTORi) promote tumor regression in genetically defined and chemically induced HNSCC animal models, and encouraging results have been recently reported. However, the mTOR-regulated targets contributing to the clinical response have not yet been identified. Here, we focused on EIF4E-BP1 (4E-BP1), a direct target of mTOR that serves as key effector for protein synthesis. A systematic analysis of genomic alterations in the PIK3CA-mTOR pathway in HNSCC revealed that 4E-BP1 is rarely mutated, but at least one 4E-BP1 gene copy is lost in over 35% of the patients with HNSCC, correlating with decreased 4E-BP1 protein expression. 4E-BP1 gene copy number loss correlated with poor disease-free and overall survival. Aligned with a tumor-suppressive role, 4e-bp1/2 knockout mice formed larger and more lesions in models of HNSCC carcinogenesis. mTORi treatment or conditional expression of a mutant 4E-BP1 that cannot be phosphorylated by mTOR was sufficient to disrupt the translation-initiation complex and prevent tumor growth. Furthermore, CRISPR/Cas9-targeted 4E-BP1 HNSCC cells resulted in reduced sensitivity to mTORi in vitro and in vivo. Overall, these findings indicate that in HNSCC, mTOR persistently restrains 4E-BP1 via phosphorylation and that mTORi can restore the tumor-suppressive function of 4E-BP1. Our findings also support 4E-BP1 expression and phosphorylation status as a mechanistic biomarker of mTORi sensitivity in patients with HNSCC. SIGNIFICANCE: These findings suggest that EIF4E-BP1 acts as a tumor suppressor in HNSCC and that 4E-BP1 dephosphorylation mediates the therapeutic response to mTORi, providing a mechanistic biomarker for future precision oncology trials.
Insights
Aberrant PI3K-mTOR pathway activation in head and neck squamous cell carcinoma (HNSCC) makes it a target for mTOR inhibitors (mTORi). EIF4E-BP1 (4E-BP1) loss correlates with poor survival, and its restoration by mTORi suggests it as a biomarker for treatment sensitivity.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Signaling Pathways
Background:
- The PI3K-mTOR pathway is frequently hyperactivated in head and neck squamous cell carcinoma (HNSCC).
- mTOR inhibitors (mTORi) show promise in preclinical HNSCC models, but the specific targets mediating clinical response remain unclear.
- EIF4E-BP1 (4E-BP1) is a direct mTOR target crucial for protein synthesis and a potential mediator of mTORi efficacy.
Purpose of the Study:
- To investigate the role of EIF4E-BP1 (4E-BP1) in HNSCC pathogenesis and its relationship with mTOR signaling.
- To determine if 4E-BP1 alterations impact sensitivity to mTOR inhibitors (mTORi).
- To evaluate 4E-BP1 as a potential biomarker for predicting response to mTORi therapy in HNSCC.
Main Methods:
- Systematic analysis of genomic alterations in the PI3K-mTOR pathway, focusing on 4E-BP1 copy number and expression in HNSCC patient samples.
- Assessment of the correlation between 4E-BP1 gene copy loss, protein expression, and patient survival outcomes.
- Functional studies using 4e-bp1/2 knockout mice and CRISPR/Cas9-edited HNSCC cells to evaluate the impact of 4E-BP1 on tumor growth and mTORi sensitivity.
Main Results:
- Over 35% of HNSCC patients exhibit 4E-BP1 gene copy loss, correlating with decreased 4E-BP1 protein expression and poorer survival.
- Loss of 4E-BP1 function promotes HNSCC development and lesion formation in preclinical models.
- Targeting 4E-BP1 in HNSCC cells reduced sensitivity to mTOR inhibitors both in vitro and in vivo.
- mTOR persistently inhibits 4E-BP1 via phosphorylation in HNSCC, and mTORi treatment restores 4E-BP1's tumor-suppressive function.
Conclusions:
- EIF4E-BP1 (4E-BP1) functions as a tumor suppressor in head and neck squamous cell carcinoma (HNSCC).
- The dephosphorylation of 4E-BP1 by mTOR is a key mechanism underlying the therapeutic response to mTOR inhibitors.
- 4E-BP1 expression and phosphorylation status can serve as a predictive biomarker for mTORi sensitivity in HNSCC patients, guiding precision oncology strategies.
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