Disruption of the HER3-PI3K-mTOR oncogenic signaling axis and PD-1 blockade as a multimodal precision immunotherapy in head and neck cancer

• Published in: Nature communications Vol. 12; no. 1; p. 2383
• Main Authors: Wang, Zhiyong, Goto, Yusuke, Allevato, Michael M., Wu, Victoria H., Saddawi-Konefka, Robert, Gilardi, Mara, Alvarado, Diego, Yung, Bryan S., O’Farrell, Aoife, Molinolo, Alfredo A., Duvvuri, Umamaheswar, Grandis, Jennifer R., Califano, Joseph A., Cohen, Ezra E. W., Gutkind, J. Silvio
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.04.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 1-Phosphatidylinositol 3-kinase; 13; 13/1; 13/95; 631/67/1665; 631/80/86; AKT protein; Animals; Antibodies; Anticancer properties; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Cancer; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Cell Proliferation - genetics; Circuits; Class I Phosphatidylinositol 3-Kinases - genetics; Class I Phosphatidylinositol 3-Kinases - metabolism; Female; Genetic screening; Head & neck cancer; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - immunology; Head and Neck Neoplasms - pathology; Human papillomavirus; Humanities and Social Sciences; Humans; Immune checkpoint; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immunotherapy; Immunotherapy - methods; Kinases; Lymphocytes; Medical prognosis; Mice; Mortality; multidisciplinary; Mutation; Otolaryngology; PD-1 protein; Phosphorylation; Precision Medicine - methods; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - metabolism; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Receptor, ErbB-3 - antagonists & inhibitors; Receptor, ErbB-3 - metabolism; Remission; Science; Science (multidisciplinary); Signal Transduction - drug effects; Signal Transduction - genetics; Signaling; siRNA; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck - drug therapy; Squamous Cell Carcinoma of Head and Neck - genetics; Squamous Cell Carcinoma of Head and Neck - immunology; Squamous Cell Carcinoma of Head and Neck - pathology; Surgery; TOR protein; TOR Serine-Threonine Kinases - metabolism; Tumor microenvironment; Tumor Microenvironment - drug effects; Tumor Microenvironment - immunology; Tyrosine; Xenograft Model Antitumor Assays
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-22619-w

Immune checkpoint blockade (ICB) therapy has revolutionized head and neck squamous cell carcinoma (HNSCC) treatment, but <20% of patients achieve durable responses. Persistent activation of the PI3K/AKT/mTOR signaling circuitry represents a key oncogenic driver in HNSCC; however, the potential immunosuppressive effects of PI3K/AKT/mTOR inhibitors may limit the benefit of their combination with ICB. Here we employ an unbiased kinome-wide siRNA screen to reveal that HER3, is essential for the proliferation of most HNSCC cells that do not harbor PIK3CA mutations. Indeed, we find that persistent tyrosine phosphorylation of HER3 and PI3K recruitment underlies aberrant PI3K/AKT/mTOR signaling in PIK3CA wild type HNSCCs. Remarkably, antibody-mediated HER3 blockade exerts a potent anti-tumor effect by suppressing HER3-PI3K-AKT-mTOR oncogenic signaling and concomitantly reversing the immune suppressive tumor microenvironment. Ultimately, we show that HER3 inhibition and PD-1 blockade may provide a multimodal precision immunotherapeutic approach for PIK3CA wild type HNSCC, aimed at achieving durable cancer remission. There is an unmet need to improve the response to immune checkpoint blockade in patients with head and neck squamous cell carcinoma (HNSCC). Here the authors show that aberrant HER3 activation sustains the proliferation of PIK3CA wild type HNSCC cells and that HER3 inhibition increases response to PD-1 blockade in HNSCC preclinical models.