mTOR Promotes Tissue Factor Expression and Activity in EGFR-Mutant Cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Mechanistic target of rapamycin (mTOR) signaling is crucial for oncogenic receptor tyrosine kinase (RTK) function.
• EGFR-mutant (EGFR-mut) non-small cell lung cancer (NSCLC) and glioblastoma (GBM) are aggressive cancers often driven by RTKs.
• The tumor microenvironment significantly influences cancer progression and treatment response.

Purpose of the Study:

• To investigate the role of mTOR in EGFR-mut NSCLC and GBM, focusing on its impact on the tumor microenvironment.
• To elucidate the novel regulatory link between mTOR complexes (mTORCs) and tissue factor (TF) in these cancers.
• To assess the therapeutic potential of targeting the mTOR-TF axis.

Main Methods:

• Utilized EGFR-mut NSCLC and GBM cell lines and patient-derived tumors.
• Applied mTORC1/2 inhibitors (AZD8055, WYE-125132, MTI-31, rapamycin) and genetic mTORC depletion.
• Analyzed TF expression, mRNA transcription, and protein degradation pathways.
• Investigated the effects of mTOR and TF inhibition on tumor microenvironment components in mouse models.
• Assessed biomarkers including fibrin, collagen, CD31, α-SMA, and M2-type tumor-associated macrophages (CD206/F4/80 ratio).

Main Results:

• TF expression is elevated in EGFR-mut NSCLC/GBM and correlates with poor prognosis.
• mTORC1/2 inhibition or depletion significantly reduced TF expression via distinct mechanisms (transcriptional vs. degradation).
• In vivo studies confirmed TF expression inhibition by mTOR inhibitors and TF antagonism by antibodies.
• Combined mTOR and TF targeting led to multifaceted tumor microenvironment remodeling, including reduced thrombosis, fibrosis, and immunosuppression.

Conclusions:

• Identified tissue factor (TF) as a functional biomarker of mTOR signaling in EGFR-mut NSCLC and GBM.
• Downregulation of the mTOR-TF axis contributes to the therapeutic efficacy of mTORC1/2 and TF-targeted agents.
• Targeting the mTOR-TF axis represents a promising therapeutic strategy for advanced EGFR-mut NSCLC and GBM by modulating the tumor microenvironment.