2. Academic Validation
  3. Bypassing cisplatin resistance in Nrf2 hyperactivated head and neck cancer through effective PI3Kinase targeting

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

  • Br J Cancer. 2025 Oct 6. doi: 10.1038/s41416-025-03189-w.
Pedram Yadollahi 1,  Kelli A McCord 2,  Yang Li 1,  Hussam Dayoub 1,  Kalil Saab 3,  Fonma Essien 1,  Sean Hyslop 2,  Emerald Kan 2,  Kazi M Ahmed 1,  Parker R Kirby 1,  Vasanta Putluri 4 5,  Chandra Shekar R Ambati 4 5,  Karthik Reddy Kami Reddy 2 4,  Patricia Castro 6,  Heath D Skinner 7,  Cristian Coarfa 2 4,  William K Decker 4 6 8,  Abdullah A Osman 9,  Rutulkumar Patel 3,  Jeffrey N Myers 9,  Stephen Y Lai 9,  Nagireddy Putluri 2 4 5,  Faye M Johnson 10,  Mitchell J Frederick 1,  William H Hudson 11 12 13,  Vlad C Sandulache 14 15 16 17
Affiliations

Affiliations

  • 1 Bobby R. Alford Department of Otolaryngology Head and Neck Surgery, Baylor College of Medicine, Houston, TX, USA.
  • 2 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
  • 3 Department of Radiation Oncology, Baylor College of Medicine, Houston, TX, USA.
  • 4 Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
  • 5 Advanced Technology Cores, Baylor College of Medicine, Houston, TX, USA.
  • 6 Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA.
  • 7 Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA, USA.
  • 8 Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA.
  • 9 Department of Head and Neck Surgery, UT MD Anderson Cancer Center, Houston, TX, USA.
  • 10 Department of Thoracic-Head and Neck Medical Oncology, UT MD Anderson Cancer Center, Houston, TX, USA.
  • 11 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. william.hudson@bcm.edu.
  • 12 Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA. william.hudson@bcm.edu.
  • 13 Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA. william.hudson@bcm.edu.
  • 14 Bobby R. Alford Department of Otolaryngology Head and Neck Surgery, Baylor College of Medicine, Houston, TX, USA. vlad.sandulache@bcm.edu.
  • 15 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. vlad.sandulache@bcm.edu.
  • 16 Department of Radiation Oncology, Baylor College of Medicine, Houston, TX, USA. vlad.sandulache@bcm.edu.
  • 17 Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA. vlad.sandulache@bcm.edu.
PMID: 41053162 DOI: 10.1038/s41416-025-03189-w
Abstract

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.

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