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

Abstract

<div>Abstract<p>Tumor suppressor mutations in head and neck squamous cell carcinoma (HNSCC) dominate the genomic landscape, hindering the development of effective targeted therapies. Truncating and missense mutations in <i>NOTCH1</i> are frequent in HNSCC, and inhibition of PI3K can selectively target <i>NOTCH1</i> mutant (<i>NOTCH1<sup>MUT</sup></i>) HNSCC cells. In this study, we identify several proteins that are differentially regulated in HNSCC cells after PI3K inhibition based on <i>NOTCH1<sup>MUT</sup></i> status. Expression of Aurora kinase B (Aurora B), AKT, and PDK1 following PI3K inhibition was significantly lower in <i>NOTCH1<sup>MUT</sup></i> cell lines than in wild-type <i>NOTCH1</i> (<i>NOTCH1<sup>WT</sup></i>) cells or <i>NOTCH1<sup>MUT</sup></i> cells with acquired resistance to PI3K inhibition. Combined inhibition of PI3K and Aurora B was synergistic, enhancing apoptosis <i>in vitro</i> and leading to durable tumor regression <i>in vivo</i>. Overexpression of Aurora B in <i>NOTCH1<sup>MUT</sup></i> HNSCC cells led to resistance to PI3K inhibition, while Aurora B knockdown increased sensitivity of <i>NOTCH1<sup>WT</sup></i> cells. In addition, overexpression of Aurora B in <i>NOTCH1<sup>MUT</sup></i> HNSCC cells increased total protein levels of AKT and PDK1. AKT depletion in <i>NOTCH1<sup>WT</sup></i> cells and overexpression in <i>NOTCH1<sup>MUT</sup></i> cells similarly altered sensitivity to PI3K inhibition, and manipulation of AKT levels affected PDK1 but not Aurora B levels. These data define a novel pathway in which Aurora B upregulates AKT that subsequently increases PDK1 selectively in <i>NOTCH1<sup>MUT</sup></i> cells to mediate HNSCC survival in response to PI3K inhibition. These findings may lead to an effective therapeutic approach for HNSCC with <i>NOTCH1<sup>MUT</sup></i> while sparing normal cells.</p>Significance:<p>Aurora B signaling facilitates resistance to PI3K inhibition in head and neck squamous cell carcinoma, suggesting that combined inhibition of PI3K and Aurora kinase is a rational therapeutic strategy to overcome resistance.</p></div>