Cancer Res. 2018 May 1;78(9):2383-2395. doi: 10.1158/0008-5472.CAN-17-1672. Epub 2018 Feb 12.
Cross-talk Signaling between HER3 and HPV16 E6 and E7 Mediates Resistance to PI3K Inhibitors in Head and Neck Cancer.
Brand TM1, Hartmann S1,2, Bhola NE1, Li H1, Zeng Y1, O'Keefe RA1, Ranall MV3, Bandyopadhyay S3, Soucheray M4, Krogan NJ4, Kemp C5, Duvvuri U5, LaVallee T6, Johnson DE1, Ozbun MA7, Bauman JE8, Grandis JR9.
1
Department of Otolaryngology - Head and Neck Surgery, University of California San Francisco, San Francisco, California.
2
Department of Oral and Maxillofacial Plastic Surgery, University Hospital Würzburg, Würzburg, Germany.
3
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California.
4
Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California.
5
Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
6
Celldex Therapeutics, New Haven, Connecticut.
7
Department of Molecular Genetics & Microbiology, University of New Mexico School of Medicine, Albuquerque, New Mexico.
8
Division of Hematology/Oncology, University of Arizona Cancer Center, Tucson, Arizona.
9
Department of Otolaryngology - Head and Neck Surgery, University of California San Francisco, San Francisco, California. jennifer.grandis@ucsf.edu.
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.Significance: These findings suggest a new therapeutic combination that may improve outcomes in HPV(+) head and neck cancer patients. |
