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Combination AURKA and WEE1 Inhibition Exhibits Efficacy in EGFR or Pan-ERBB Inhibitor-Resistant Head and Neck

Flaviane N Silva1,2, Jong Woo Lee3, Theodore T Nguyen1,2

  • 1Cancer Signaling and Microenvironment Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Cancer Research Communications
|July 30, 2026
PubMed

Insights

Head and neck squamous cell carcinoma (HNSCC) treatments face resistance. Combining Aurora kinase A (AURKA) and WEE1 inhibitors shows promise for overcoming resistance in HNSCC. This strategy may benefit patients with ERBB inhibitor-resistant tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Head and neck squamous cell carcinoma (HNSCC) affects over 600,000 people globally each year.
  • Epidermal Growth Factor Receptor (EGFR) inhibitors and pan-ERBB inhibitors (ERBBis) are used for advanced HNSCC, but resistance often develops, linked to epithelial-mesenchymal transition (EMT).
  • Aurora kinase A (AURKA) has shown potential in overcoming EGFR resistance in lung cancer.

Purpose of the Study:

  • To develop and characterize HNSCC models resistant to EGFR inhibitors (EGFRis) and ERBBis.
  • To investigate strategies for overcoming resistance to EGFRis and ERBBis in HNSCC.
  • To evaluate the efficacy of combining AURKA inhibitors with WEE1 inhibitors in HNSCC models.

Main Methods:

  • Established HNSCC cell models, including treatment-naïve parental and erlotinib- or afatinib-resistant lines.
  • Assessed the impact of partial epithelial-mesenchymal transition (EMT) and NEDD9 upregulation in resistant models.
  • Utilized short-term growth assays, long-term clonogenic assays, and in vivo xenograft models to evaluate drug synergy and sensitivity.
  • Tested combinations of AURKA inhibitor (VIC-1911) with EGFRi (erlotinib), ERBBi (afatinib), and WEE1 inhibitor (adavosertib).

Main Results:

  • Resistant HNSCC models exhibited partial EMT and increased NEDD9.
  • Initial synergy between VIC-1911 and erlotinib/afatinib was reduced in resistant models.
  • Resistant cells showed heightened sensitivity to VIC-1911 in long-term assays and in vivo.
  • Combination of VIC-1911 and adavosertib demonstrated efficacy in vitro and in vivo, including in ERBBi-resistant xenografts.

Conclusions:

  • HNSCC resistance to EGFR/ERBB inhibitors is associated with increased AURKA dependence.
  • Combined inhibition of AURKA and WEE1 offers a potential therapeutic strategy for ERBB inhibitor-resistant HNSCC.
  • This combination warrants further investigation for clinical application in HNSCC patients.

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