Everolimus downregulates STAT3/HIF-1α/VEGF pathway to inhibit angiogenesis and lymphangiogenesis in TP53 mutant head and neck squamous cell carcinoma (HNSCC)

• Published in: Oncotarget 2023-02, Vol.14 (1), p.85-95
• Main Authors: Alam, Md Maksudul, Fermin, Janmaris Marin, Knackstedt, Mark, Noonan, Mackenzie J, Powell, Taylor, Goodreau, Landon, Daniel, Emily K, Rong, Xiaohua, Moore-Medlin, Tara, Khandelwal, Alok R, Nathan, Cherie-Ann O
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Everolimus - pharmacology; Everolimus - therapeutic use; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - genetics; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Lymphangiogenesis; Mice; Mice, Nude; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Research Paper; Squamous Cell Carcinoma of Head and Neck - drug therapy; Squamous Cell Carcinoma of Head and Neck - genetics; STAT3 Transcription Factor - metabolism; TOR Serine-Threonine Kinases - metabolism; Tumor Suppressor Protein p53 - genetics; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.28355

mutant head and neck squamous cell carcinoma (HNSCC) patients exhibit poor clinical outcomes with 50-60% recurrence rates in advanced stage patients. In a recent phase II clinical trial, adjuvant therapy with everolimus (mTOR inhibitor) significantly increased 2-year progression-free survival in p53 mutated patients. TP53-driven mTOR activation in solid malignancies causes upregulation of HIF-1α and its target, downstream effector VEGF, by activating STAT3 cell signaling pathway. Here, we investigated the effects of everolimus on the STAT3/HIF-1α/VEGF pathway in mutant cell lines and xenograft models. Treatment with everolimus significantly inhibited cell growth and effectively reduced the growth of mutant xenografts in a minimal residual disease (MRD) model in nude mice. Everolimus treatment was associated with significant downregulation of STAT3/HIF-1α/VEGF pathway in both models. Further, treatment with everolimus was associated with attenuation in tumor angiogenesis and lymphangiogenesis as indicated by decreased microvessel density of vascular and lymphatic vessels in HN31 and FaDu xenografts. Everolimus downregulated the STAT3/HIF-1α/VEGF pathway to inhibit growth and tube formation of HMEC-1 (endothelial) and HMEC-1A (lymphatic endothelial) cell lines. Our studies demonstrated that everolimus inhibits the growth of mutant tumors by inhibiting angiogenesis and lymphangiogenesis through the downregulation of STAT3/HIF-1α/VEGF signaling.