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

  • bioRxiv. 2025 Jan 16:2025.01.10.632413. doi: 10.1101/2025.01.10.632413.
P Yadollahi 1,  K A McCord 2,  Y Li 1,  H Dayoub 1,  K Saab 3,  F Essien 1,  S Hyslop 2,  E Kan 2,  K M Ahmed 1,  P R Kirby 1,  V Putluri 2 4 5,  C S R Ambati 2 4 5,  K R Kami Reddy 2 4 5,  P Castro 6,  H D Skinner 7,  C Coarfa 2 4,  W K Decker 6,  A A Osman 8,  R Patel 3,  J N Myers 8,  S Y Lai 8,  N Putluri 2 4 5,  F M Johnson 9,  M J Frederick 1,  W H Hudson 2 4 10,  V C Sandulache 1 2 11
Affiliations

Affiliations

  • 1 Bobby R. Alford Department of Otolaryngology Head and Neck Surgery, Baylor College of Medicine, Houston, TX.
  • 2 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX.
  • 3 Department of Radiation Oncology, Baylor College of Medicine, Houston, TX.
  • 4 Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX.
  • 5 Advanced Technology Cores, Baylor College of Medicine, Houston, TX.
  • 6 Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX.
  • 7 Department of Radiation Oncology, UPMC Hillman Cancer Center, Pittsburgh, PA.
  • 8 Department of Head and Neck Surgery, UT MD Anderson Cancer Center, Houston, TX.
  • 9 Department of Thoracic-Head and Neck Medical Oncology, UT MD Anderson Cancer Center, Houston, TX.
  • 10 Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX.
  • 11 Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX.
PMID: 39868226 DOI: 10.1101/2025.01.10.632413
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).

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 in vitro and tested efficacy in vivo 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 in vivo 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.

Keywords

NRF2; copanlisib; gedatolisib; head and neck cancer.

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