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HPV E2, E4, E5 drive alternative carcinogenic pathways in HPV positive cancers

Ren, Shuling, Gaykalova, Daria A., Guo, Theresa, Favorov, Alexander V., Fertig, Elana J., Tamayo, Pablo, Callejas-Valera, Juan Luis, Allevato, Mike, Gilardi, Mara, Santos, Jessica, Fukusumi, Takahito, Sakai, Akihiro, Ando, Mizuo, Sadat, Sayed, Liu, Chao, Xu, Guorong, Fisch, Kathleen M., Wang, Zhiyong, Molinolo, Alfredo A., Gutkind, J. Silvio, Ideker, Trey, Koch, Wayne M., Califano, Joseph A.·2020·Oncogene
DOI 10.1038/s41388-020-01431-8PMC PMC7529583
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Abstract

The dominant paradigm for HPV carcinogenesis includes integration into the host genome followed by expression of E6 and E7 (E6/E7). We explored an alternative carcinogenic pathway characterized by episomal E2, E4, and E5 (E2/E4/E5) expression. Half of HPV positive cervical and pharyngeal cancers comprised a subtype with increase in expression of E2/E4/E5, as well as association with lack of integration into the host genome. Models of the E2/E4/E5 carcinogenesis show p53 dependent enhanced proliferation in vitro, as well as increased susceptibility to induction of cancer in vivo. Whole genomic expression analysis of the E2/E4/E5 pharyngeal cancer subtype is defined by activation of the fibroblast growth factor receptor (FGFR) pathway and this subtype is susceptible to combination FGFR and mTOR inhibition, with implications for targeted therapy.

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Cited by

Metadata

Authors
Ren, S., Gaykalova, D. A., Guo, T., Favorov, A. V., Fertig, E. J., Tamayo, P., Callejas-Valera, J. L., Allevato, M., Gilardi, M., Santos, J., Fukusumi, T., Sakai, A., Ando, M., Sadat, S., Liu, C., Xu, G., Fisch, K. M., Wang, Z., Molinolo, A. A., Gutkind, J. S., Ideker, T., Koch, W. M., & Califano, J. A.
ORCID
Venue
Oncogene
Publisher
Springer Science and Business Media LLC
Published
2020-08-26
Volume
39
Issue
40
Pages
6327-6339
ISSN
  • 0950-9232
  • 1476-5594
DOI
10.1038/s41388-020-01431-8
PMC
PMC7529583
Cited by
93
References
1
Language
en
Licence
Funders
  • U.S. Department of Health & Human Services | National Institutes of Health (P30 CA006973)
  • Russian Foundation for Basic Research (17-00-00208)
  • Russian Academy of Sciences (0112-2019-0001)

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