@article{f8e63912e157461ca81bd95ba0bde034,
title = "Cross-talk signaling between HER3 and HPV16 E6 and E7 mediates resistance to PI3K inhibitors in head and neck cancer",
abstract = "Human papillomavirus (HPV) type 16 is implicated in approximately 75% of head and neck squamous cell carcinomas (HNSCC) that arise in the oropharynx, where viral expression of the E6 and E7 oncoproteins promote cellular transformation, tumor growth, and maintenance. An important oncogenic signaling pathway activated by E6 and E7 is the PI3K pathway, a key driver of carcinogenesis. The PI3K pathway is also activated by mutation or amplification of PIK3CA in over half of HPV({\th}) HNSCC. In this study, we investigated the efficacy of PI3K-targeted therapies in HPV({\th}) HNSCC preclinical models and report that HPV({\th}) cell line- and patient-derived xenografts are resistant to PI3K inhibitors due to feedback signaling emanating from E6 and E7. Receptor tyrosine kinase profiling indicated that PI3K inhibition led to elevated expression of the HER3 receptor, which in turn increased the abundance of E6 and E7 to promote PI3K inhibitor resistance. Targeting HER3 with siRNA or the mAb CDX-3379 reduced E6 and E7 abundance and enhanced the efficacy of PI3K-targeted therapies. Together, these findings suggest that cross-talk between HER3 and HPV oncoproteins promotes resistance to PI3K inhibitors and that cotargeting HER3 and PI3K may be an effective therapeutic strategy in HPV({\th}) tumors. Significance: These findings suggest a new therapeutic combination that may improve outcomes in HPV({\th}) head and neck cancer patients.",
author = "Brand, {Toni M.} and Stefan Hartmann and Bhola, {Neil E.} and Hua Li and Yan Zeng and O'Keefe, {Rachel A.} and Ranall, {Max V.} and Sourav Bandyopadhyay and Margaret Soucheray and Krogan, {Nevan J.} and Carolyn Kemp and Umamaheswar Duvvuri and Theresa LaVallee and Johnson, {Daniel E.} and Ozbun, {Michelle A.} and Bauman, {Julie E.} and Grandis, {Jennifer R.}",
note = "Funding Information: The authors thank Dr. Danielle Swaney (University of California, San Francisco, San Francisco, CA) for critically reviewing this manuscript. The project described was supported by RO1 DE023685 from the National Cancer Institute (to J. Grandis), the American Cancer Society (to J. Grandis), the V Foundation for Cancer Research (to J.E. Bauman), Career Development Award CDA-2-057-10S from the Department of Veterans Affairs (to U. Duvvuri), grant Z-2/59 from the Interdisciplinary Center for Clinical Research of the University Wurzburg € (to S. Hartmann), postdoctoral fellowship PF-16-087-01-TBG from the American Cancer Society (to T.M. Brand), by NIH grant T32 CA108462 for Molecular and Cellular Mechanisms of Disease (to T.M. Brand), and U54 CA209891 (to N.J. Krogan). Funding Information: The authors thank Dr. Danielle Swaney (University of California, San Francisco, San Francisco, CA) for critically reviewing this manuscript. The project described was supported by RO1 DE023685 from the National Cancer Institute (to J. Grandis), the American Cancer Society (to J. Grandis), the V Foundation for Cancer Research (to J.E. Bauman), Career Development Award CDA-2-057-10S from the Department of Veterans Affairs (to U. Duvvuri), grant Z-2/59 from the Interdisciplinary Center for Clinical Research of the University Wu€rzburg (to S. Hartmann), postdoctoral fellowship PF-16-087-01-TBG from the American Cancer Society (to T.M. Brand), by NIH grant T32 CA108462 for Molecular and Cellular Mechanisms of Disease (to T.M. Brand), and U54 CA209891 (to N.J. Krogan). Funding Information: The authors thank Dr. Danielle Swaney (University of California, San Francisco, San Francisco, CA) for critically reviewing this manuscript. The project described was supported by RO1 DE023685 from the National Cancer Institute (to J. Grandis), the American Cancer Society (to J. Grandis), the V Foundation for Cancer Research (to J.E. Bauman), Career Development Award CDA-2-057-10S from the Department of Veterans Affairs (to U. Duvvuri), grant Z-2/59 from the Interdisciplinary Center for Clinical Research of the University Wurzburg ? (to S. Hartmann), postdoctoral fellowship PF-16-087-01-TBG from the American Cancer Society (to T.M. Brand), by NIH grant T32 CA108462 for Molecular and Cellular Mechanisms of Disease (to T.M. Brand), and U54 CA209891 (to N.J. Krogan). Publisher Copyright: {\textcopyright} 2018 American Association for Cancer Research.",
year = "2018",
month = may,
day = "1",
doi = "10.1158/0008-5472.CAN-17-1672",
language = "English (US)",
volume = "78",
pages = "2383--2395",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "9",
}