Bypassing cisplatin resistance in Nrf2 hyperactivated head and neck cancer through effective PI3Kinase targeting.

BACKGROUND: For patients with head and neck squamous cell carcinoma (HNSCC), failure of definitive radiation combined with cisplatin nearly universally results in death. Although hyperactivation of the Nrf2 pathway can drive radiation and cisplatin resistance along with suppressed anti-tumor immunity, treatment-refractory HNSCC tumors may retain sensitivity to targeted agents secondary to synergistic lethality with other oncogenic drivers (e.g., NOTCH1 mutations). METHODS: Using state of the science mechanistic, metabolomic and spatial transcriptomic approaches combined with preclinical models of HNSCC, we tested whether a novel PI3K inhibitor, gedatolisib, can bypass hyperactivation of the Nrf2 pathway. RESULTS: The PI3K pathway is activated in Nrf2-driven cisplatin-resistant HNSCC and is suitable for blockade, as demonstrated in an in vivo shRNA screen with platinum-based chemotherapy. Gedatolisib effectiveness appears mediated through activation of autophagy, G2/M arrest, senescence and disruption of fatty acid metabolism. Gedatolisib suppresses HNSCC tumor growth in orthotopic and metastatic settings and demonstrates profound anti-tumor activity in humanized murine models of HNSCC, coupled with a reduction in hypoxia-rich regions and reduced infiltration by regulatory T-lymphocytes. CONCLUSIONS: These findings emphasize the critical role of the PI3K-AKT-mTOR pathway in chemo-radiation resistant HNSCC and highlight the therapeutic potential of PI3K inhibitors in a disease that is refractory to all conventional therapeutic approaches.