Radiation Enhancement of Head and Neck Squamous Cell Carcinoma by the Dual PI3K/mTOR Inhibitor PF-05212384

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Andrew J LeikerJames B Mitchell

Abstract

Radiation remains a mainstay for the treatment of nonmetastatic head and neck squamous cell carcinoma (HNSCC), a malignancy characterized by a high rate of PI3K/mTOR signaling axis activation. We investigated the ATP-competitive dual PI3K/mTOR inhibitor, PF-05212384, as a radiosensitizer in preclinical HNSCC models. Extent of radiation enhancement of two HNSCC cell lines (UMSCC1-wtP53 and UMSCC46-mtP53) and normal human fibroblast (1522) was assessed by in vitro clonogenic assay with appropriate target inhibition verified by immunoblotting. Radiation-induced DNA damage repair was evaluated by γH2AX Western blots with the mechanism of DNA double-strand break repair abrogation investigated by cell cycle analysis, immunoblotting, and RT-PCR. PF-05212384 efficacy in vivo was assessed by UMSCC1 xenograft tumor regrowth delay, xenograft lysate immunoblotting, and tissue section immunohistochemistry. PF-05212384 effectively inhibited PI3K and mTOR, resulting in significant radiosensitization of exponentially growing and plateau-phase cells with 24-hour treatment following irradiation, and variable radiation enhancement with 24-hour treatment before irradiation. Tumor cells radiosensitized to a greater extent than normal human fibrobla...Continue Reading

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Citations

Nov 26, 2015·Advanced Drug Delivery Reviews·Daniel R Wahl, Theodore S Lawrence
Jul 7, 2019·Journal of Hematology & Oncology·Hui HuaYangfu Jiang
Feb 14, 2019·International Journal of Molecular Sciences·Tian TianJinhua Zhang
Sep 10, 2020·Frontiers in Oncology·Katharina HintelmannThorsten Rieckmann
May 3, 2018·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Sarwat NazJames B Mitchell
Jul 10, 2019·IScience·Joe Truong NguyenPaul H Krebsbach
Dec 1, 2020·Clinical and Translational Radiation Oncology·George D WilsonSandra Galoforo
Nov 1, 2020·Translational Oncology·Shilpi GuptaBhudev C Das
Feb 18, 2020·Biochimica Et Biophysica Acta. Molecular Cell Research·Michelle J LeeDaniel E Johnson
Aug 7, 2021·Molecular Biology Reports·Alireza MardanshahiSajjad Molavipordanjani

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