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Sustained Aurora Kinase B Expression Confers Resistance to PI3K Inhibition in Head and Neck Squamous Cell Carcinoma

Pooja A Shah1, Vaishnavi Sambandam1, Anne M Fernandez1

  • 1Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Cancer Research
|September 28, 2022
PubMed

Insights

Targeting head and neck squamous cell carcinoma (HNSCC) with NOTCH1 mutations is challenging. Combining PI3K and Aurora kinase B inhibition shows promise for effective treatment by overcoming resistance and promoting tumor regression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genomics

Background:

  • Head and neck squamous cell carcinoma (HNSCC) frequently harbors tumor suppressor mutations, complicating targeted therapy development.
  • NOTCH1 mutations are common in HNSCC, and PI3K inhibition shows selective efficacy against NOTCH1-mutant (NOTCH1MUT) cells.

Purpose of the Study:

  • To identify proteins differentially regulated in HNSCC cells following PI3K inhibition, stratified by NOTCH1 mutation status.
  • To elucidate the role of Aurora kinase B (Aurora B) in mediating resistance to PI3K inhibition in HNSCC.
  • To evaluate the therapeutic potential of combined PI3K and Aurora B inhibition in HNSCC.

Main Methods:

  • Proteomic analysis of HNSCC cell lines with varying NOTCH1 mutation status and PI3K inhibition.
  • In vitro and in vivo studies assessing the synergistic effects of combined PI3K and Aurora B inhibition.
  • Genetic manipulation (overexpression and knockdown) of Aurora B and AKT to determine pathway interactions.

Main Results:

  • Expression of Aurora B, AKT, and PDK1 was significantly lower in NOTCH1MUT HNSCC cells post-PI3K inhibition compared to wild-type or resistant cells.
  • Combined PI3K and Aurora B inhibition demonstrated synergistic apoptosis in vitro and durable tumor regression in vivo.
  • Aurora B overexpression conferred resistance to PI3K inhibition in NOTCH1MUT cells, while knockdown sensitized NOTCH1WT cells.
  • A novel pathway was identified where Aurora B upregulates AKT, subsequently increasing PDK1, mediating HNSCC survival in response to PI3K inhibition.

Conclusions:

  • Aurora B signaling drives resistance to PI3K inhibition in HNSCC by upregulating the AKT/PDK1 pathway, particularly in NOTCH1MUT cells.
  • Combined inhibition of PI3K and Aurora B represents a rational and potentially effective therapeutic strategy for HNSCC.
  • This approach may offer a targeted therapy for NOTCH1MUT HNSCC while sparing normal tissues.

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