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., mutations).

Purpose: We evaluated the efficacy of PI3K inhibitors (PI3Ki) in bypassing Nrf2-mediated cisplatin resistance in HNSCC.

Methods: We measured transcriptomic, metabolomic and signaling changes driven by PI3Kis in cisplatin-resistant HNSCCs and tested efficacy in subcutaneous, orthotopic and metastatic xenograft models using immunodeficient and humanized murine models of HNSCC coupled with spatial transcriptomics.

Results: The PI3K pathway is activated in Nrf2-driven cisplatin-resistant HNSCC and is suitable for blockade as demonstrated in an shRNA screen. The PI3Ki gedatolisib inhibits cisplatin-resistant HNSCC proliferation, induces G2M arrest and potentiates cisplatin effectiveness through activation of autophagy, 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.

Conclusion: Our findings emphasize the critical role of the PI3K-AKT-mTOR pathway in cisplatin-resistant HNSCC and highlight the therapeutic potential of PI3K inhibitors. Gedatolisib induced metabolic regulation and substantial re-sensitization of resistant cells to cisplatin, positioning it as a promising candidate for combination therapies aimed at overcoming primary chemo-radiation failure in HNSCC.

Statement Of Translational Relevance: Cisplatin resistance, whether intrinsic or acquired, translates to treatment failure and nearly universal death in head and neck squamous cell carcinoma (HNSCC). However, the development of effective systemic regimens for cisplatin-resistant HNSCC has not yet been successful. Here, we present, for the first time, a mechanistic, biomarker-informed strategy for effective targeting of the PI3Kinase pathway in cisplatin-resistant HNSCC with substantial anti-tumor activity in both orthotopic and metastatic models, which may be capable of bypassing or reversing cisplatin resistance in this disease.