TitleCross-talk Signaling between HER3 and HPV16 E6 and E7 Mediates Resistance to PI3K Inhibitors in Head and Neck Cancer.
Publication TypeJournal Article
Year of Publication2018
AuthorsBrand TM, Hartmann S, Bhola NE, Li H, Zeng Y, O'Keefe RA, Ranall MV, Bandyopadhyay S, Soucheray M, Krogan NJ, Kemp C, Duvvuri U, LaVallee T, Johnson DE, Ozbun MA, Bauman JE, Grandis JR
JournalCancer Res
Volume78
Issue9
Pagination2383-2395
Date Published2018 May 01
ISSN1538-7445
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(+) HNSCC. In this study, we investigated the efficacy of PI3K-targeted therapies in HPV(+) HNSCC preclinical models and report that HPV(+) 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(+) tumors. These findings suggest a new therapeutic combination that may improve outcomes in HPV(+) head and neck cancer patients. .

DOI10.1158/0008-5472.CAN-17-1672
Alternate JournalCancer Res.
PubMed ID29440171
Grant ListR01 DE023685 / DE / NIDCR NIH HHS / United States