mTOR inhibition as an adjuvant therapy in a metastatic model of HPV+ HNSCC

Joseph D. Coppock, Paola D. Vermeer, Daniel W. Vermeer, Kimberly M. Lee, W. Keith Miskimins, William C. Spanos, John H. Lee

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Effective treatments for recurrent/metastatic human papillomavirus-positive (HPV+) head and neck squamous cell cancer (HNSCC) are limited. To aid treatment development, we characterized a novel murine model of recurrent/metastatic HPV+ HNSCC. Further analysis of the parental tumor cell line and its four recurrent/ metastatic derivatives led to preclinical testing of an effective treatment option for this otherwise fatal disease. Reverse phase protein arrays identified key signaling cascades in the parental and recurrent/metastatic cell lines. While protein expression profiles differed among the recurrent/metastatic cell lines, activated proteins associated with the mTOR signaling cascade were a commonality. Based on these data, mTOR inhibition was evaluated as an adjuvant treatment for recurrent/metastatic disease. mTOR activity and treatment response were assessed in vitro by western blot, Seahorse, proliferation, clonogenic, and migration assays. Standard-of-care cisplatin/ radiation therapy (CRT) versus CRT/rapamycin were compared in vivo. Low-dose rapamycin inhibited mTOR signaling, decreasing proliferation (43%) and migration (62%) while it enhanced CRT-induced cytotoxicity (3.3 fold) in clonogenic assays. Furthermore, rapamycin re-sensitized CRT-resistant, metastatic tumors to treatment in vivo, improving long-term cures (0-30% improved to 78-100%, depending on the recurrent/metastatic cell line) and limiting lymph node metastasis (32%) and lung metastatic burden (30 fold). Studies using immune compromised mice suggested rapamycin's effect on metastasis is independent of the adaptive immune response. These data suggest a role of mTOR activation in HPV+ HNSCC recurrent/metastatic disease and that adjuvant mTOR inhibition may enhance treatment of resistant, metastatic cell populations at the primary site and limit distant metastasis.

Original languageEnglish (US)
Pages (from-to)24228-24241
Number of pages14
JournalOncotarget
Volume7
Issue number17
DOIs
StatePublished - Apr 26 2016

Keywords

  • Head and neck oral cancer
  • Human papillomavirus
  • Metastasis
  • Rapamycin
  • mTOR

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Coppock, J. D., Vermeer, P. D., Vermeer, D. W., Lee, K. M., Miskimins, W. K., Spanos, W. C., & Lee, J. H. (2016). mTOR inhibition as an adjuvant therapy in a metastatic model of HPV+ HNSCC. Oncotarget, 7(17), 24228-24241. https://doi.org/10.18632/oncotarget.8286