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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Proliferation / genetics
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Class I Phosphatidylinositol 3-Kinases / genetics
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Class I Phosphatidylinositol 3-Kinases / metabolism
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Female
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Head and Neck Neoplasms / drug therapy*
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Head and Neck Neoplasms / genetics
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Head and Neck Neoplasms / immunology
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Head and Neck Neoplasms / pathology
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Humans
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Immune Checkpoint Inhibitors / pharmacology
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Immune Checkpoint Inhibitors / therapeutic use
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Immunotherapy / methods
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Mice
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Mutation
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Precision Medicine / methods
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Programmed Cell Death 1 Receptor / antagonists & inhibitors*
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Programmed Cell Death 1 Receptor / metabolism
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use
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Receptor, ErbB-3 / antagonists & inhibitors*
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Receptor, ErbB-3 / metabolism
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Squamous Cell Carcinoma of Head and Neck / drug therapy*
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Squamous Cell Carcinoma of Head and Neck / genetics
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Squamous Cell Carcinoma of Head and Neck / immunology
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Squamous Cell Carcinoma of Head and Neck / pathology
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TOR Serine-Threonine Kinases / metabolism
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Tumor Microenvironment / drug effects
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Tumor Microenvironment / immunology
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Xenograft Model Antitumor Assays
Substances
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Immune Checkpoint Inhibitors
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PDCD1 protein, human
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Programmed Cell Death 1 Receptor
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Protein Kinase Inhibitors
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MTOR protein, human
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Class I Phosphatidylinositol 3-Kinases
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PIK3CA protein, human
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ERBB3 protein, human
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Receptor, ErbB-3
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TOR Serine-Threonine Kinases