Human Papillomavirus Regulates HER3 Expression in Head and Neck Cancer: Implications for Targeted HER3 Therapy in HPV+ Patients

Abstract

Purpose Human papillomavirus (HPV) 16 plays an etiologic role in a growing subset of HNSCCs, where viral expression of the E6 and E7 oncoproteins are necessary for tumor growth and maintenance. Although patients with HPV(+) tumors have a more favorable prognosis, there are currently no HPV-selective therapies. Recent studies identified differential receptor tyrosine kinase (RTK) profiles in HPV(+) vs. HPV(−) tumors. One such RTK, HER3, is overexpressed and interacts with phosphoinositide 3-kinase (PI3K) in HPV(+) tumors. Therefore, we investigated the role of HPV oncoproteins in regulating HER3-mediated signaling, and determined whether HER3 could be a molecular target in HPV(+) HNSCCs. Experimental Design HER3 was investigated as a molecular target in HPV(+) HNSCC using established cell lines, patient-derived xenografts (PDX), and human tumor specimens. A mechanistic link between HPV and HER3 was examined by augmenting E6 and E7 expression levels in HNSCC cell lines. The dependency of HPV(+) and HPV(−) HNSCC models on HER3 was evaluated with anti-HER3 siRNAs and the clinical stage anti-HER3 monoclonal antibody KTN3379. Results HER3 was overexpressed in HPV(+) HNSCCs, where it was associated with worse overall survival in patients with pharyngeal cancer. Further investigation indicated that E6 and E7 regulated HER3 protein expression and downstream PI3K pathway signaling. Targeting HER3 with siRNAs or KTN3379 significantly inhibited the growth of HPV(+) cell lines and PDXs. Conclusions This study uncovers a direct relationship between HPV infection and HER3 in HNSCC, and provides rationale for the clinical evaluation of targeted HER3 therapy for the treatment of HPV(+) patients.

Molecular mechanisms of human papillomavirus-related carcinogenesis in head and neck cancer

“…The discrepancy was addressed with a recent study investigating the relationship between HPV oncoproteins and HER3-mediated signaling, and the role of HER3 as a potential molecular target in HPV-positive HNSCC [97]. This study proposed a novel mechanism by which HPV can promote tumor growth through the mTOR/AKT/PI3K pathway.…”

“…They found that E6/E7 gene silencing led to diminished HER3 production, while increased E6/E7 oncoprotein production led to increased HER3 production. The results indicate a relationship between HPV infection and HER3 expression that is mediated by the E6 and E7 oncoproteins [97]. …”

“…Their suspicions were confirmed; genetic ablation of HER3 resulted in statistically significant inhibition of cellular proliferation (21–55%) [97]. Furthermore, HER3 knockdown led to reduced AKT and RPS6 phosphorylation [97].…”

“…Their suspicions were confirmed; genetic ablation of HER3 resulted in statistically significant inhibition of cellular proliferation (21–55%) [97]. Furthermore, HER3 knockdown led to reduced AKT and RPS6 phosphorylation [97]. The reduction of these proteins, which are components of the same mTOR/AKT/PI3K pathway discussed in the genomics section of this review, suggests that HER3 exerts its proliferative effect by signaling through the mTOR/AKT/PI3K signaling pathway [97].…”

“…KTN3379 was shown to be effective in growth inhibition in 4 out of 4 HPV-positive HNSCC cell lines, versus 2 out of 5 HPV- lines [97]. KTN3379 inhibited phosphorylation of HER3 in all HNSCC cell lines regardless of HPV status, but analysis of downstream PI3K signaling revealed that phospho-AKT and phospho-RPS6 were more significantly inhibited in three HPV-positive cell lines versus three HPV-negative cell lines [97].…”