Patient-derived xenograft models of Fanconi anemia-associated head and neck cancer identify personalized therapeutic strategies

J Clin Invest. 2025 Dec 16;136(4):e195334. doi: 10.1172/JCI195334. eCollection 2026 Feb 16.

Abstract

Fanconi anemia (FA) confers a high risk (~700-fold increase) of solid tumor formation, most often head and neck squamous cell carcinoma (HNSCC). FA germline DNA repair defects preclude administration of most chemotherapies, and prior hematopoietic stem cell transplantation limits the use of immunotherapy. Thus, surgery and judicious delivery of radiation offer the only treatment options, with most patients dying from their cancers. A paucity of preclinical models has limited the development of new treatments. Here, we report what to our knowledge are the first patient-derived xenografts (PDXs) of FA-associated HNSCC (FA-HNSCC) and highlight the efficacy of FDA-approved EGFR-targeted therapies in tumors with high EGFR and phosphorylated EGFR levels and the activity of the FDA-approved B-cell lymphoma 2 (Bcl-2) inhibitor venetoclax in a FA-HNSCC PDX overexpressing Bcl-2. These findings support the development of precision medicine approaches for FA-HNSCC.

Keywords: Genetics; Head and neck cancer; Oncology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bridged Bicyclo Compounds, Heterocyclic
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Fanconi Anemia* / complications
  • Fanconi Anemia* / genetics
  • Fanconi Anemia* / metabolism
  • Fanconi Anemia* / pathology
  • Fanconi Anemia* / therapy
  • Female
  • Head and Neck Neoplasms* / drug therapy
  • Head and Neck Neoplasms* / genetics
  • Head and Neck Neoplasms* / metabolism
  • Head and Neck Neoplasms* / pathology
  • Head and Neck Neoplasms* / therapy
  • Humans
  • Male
  • Mice
  • Precision Medicine*
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Squamous Cell Carcinoma of Head and Neck* / drug therapy
  • Squamous Cell Carcinoma of Head and Neck* / genetics
  • Squamous Cell Carcinoma of Head and Neck* / metabolism
  • Squamous Cell Carcinoma of Head and Neck* / pathology
  • Squamous Cell Carcinoma of Head and Neck* / therapy
  • Sulfonamides* / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • venetoclax
  • EGFR protein, human
  • Sulfonamides
  • Proto-Oncogene Proteins c-bcl-2
  • ErbB Receptors
  • BCL2 protein, human
  • Bridged Bicyclo Compounds, Heterocyclic