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- Title
Disruption of the HER3-PI3K-mTOR oncogenic signaling axis and PD-1 blockade as a multimodal precision immunotherapy in head and neck cancer.
- 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
- Abstract
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.
- Subjects
HEAD &; neck cancer; PROGRAMMED cell death 1 receptors; IMMUNE checkpoint inhibitors; CANCER remission; SQUAMOUS cell carcinoma; DENDRITIC cells; ONCOGENES
- Publication
Nature Communications, 2021, Vol 12, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-021-22619-w