Research Papers:

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

Md Maksudul Alam, Janmaris Marin Fermin, Mark Knackstedt, Mackenzie J. Noonan, Taylor Powell, Landon Goodreau, Emily K. Daniel, Xiaohua Rong, Tara Moore-Medlin, Alok R. Khandelwal and Cherie-Ann O. Nathan _

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Md Maksudul Alam1, Janmaris Marin Fermin1, Mark Knackstedt1, Mackenzie J. Noonan1, Taylor Powell2, Landon Goodreau2, Emily K. Daniel1, Xiaohua Rong1, Tara Moore-Medlin1,3, Alok R. Khandelwal1,3 and Cherie-Ann O. Nathan1,3

1 Department of Otolaryngology-Head and Neck Surgery, LSU-Health Sciences Center, Shreveport, LA 71103, USA

2 School of Medicine, LSU-Health Sciences Center, Shreveport, LA 71103, USA

3 Feist-Weiller Cancer Center, LSU-Health Sciences Center, Shreveport, LA 71103, USA

Correspondence to:

Cherie-Ann O. Nathan, email: [email protected]

Keywords: TP53 mutant; HNSCC; angiogenesis; everolimus; mTOR

Received: November 07, 2022     Accepted: January 23, 2023     Published: February 02, 2023

Copyright: © 2023 Alam et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


TP53 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 TP53 mutant cell lines and xenograft models. Treatment with everolimus significantly inhibited cell growth in vitro and effectively reduced the growth of TP53 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 in vitro tube formation of HMEC-1 (endothelial) and HMEC-1A (lymphatic endothelial) cell lines. Our studies demonstrated that everolimus inhibits the growth of TP53 mutant tumors by inhibiting angiogenesis and lymphangiogenesis through the downregulation of STAT3/HIF-1α/VEGF signaling.

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