Mechanistic target of
rapamycin (mTOR) signaling pathway mediates the function of oncogenic
receptor tyrosine kinases (RTKs). We aimed to elucidate new role of mTOR in EGFR-mutant (EGFR-mut)
non-small cell lung cancer (NSCLC) and
glioblastoma (GBM) with a focus on tumor microenvironments. Here, we report a novel regulatory link between mTOR complexes (mTORCs) and
tissue factor (TF), an initiator of
tumor-derived
thrombosis. TF is elevated in EGFR-mut NSCLC/GBM cell lines and
tumors from patients with poor prognosis. Application of
mTORC1/2 inhibitors (
AZD8055,
WYE-125132, MTI-31, and
rapamycin) or genetic mTORC-depletion all reduced TF expression, which appeared to be differentially mediated depending on cellular context. In U87MG and HCC827 cells,
mTORC1 exerted a dominant role via promoting TF
mRNA transcription. In EGFR-TKI-resistant H1975 and PC9 cells, it was
mTORC2 that played a major role in specific repression of lysosomal-targeted TF protein degradation. Successful inhibition of TF expression was demonstrated in AZD8055- or MTI-31-treated H1975 and U87MG
tumors in mice, while a TF-targeted antibody antagonized TF activity without reducing TF
protein. Both the mTOR- and TF-targeted
therapy induced a multifaceted remodeling of tumor microenvironment reflecting not only a diminished hypercoagulopathy state (
fibrin level) but also a reduced stromal
fibrosis (
collagen distribution), compromised vessel density and/or maturity (CD31 and/or α-SMA) as well as a substantially decreased infiltration of immune-suppressive M2-type tumor-associated macrophages (CD206/F4/80 ratio). Thus, our results have identified TF as a functional
biomarker of mTOR. Downregulation of mTOR-TF axis activity likely contributes to the therapeutic mechanism of
mTORC1/2- and TF-targeted agents in EGFR-mut advanced NSCLC and GBM.