Abstract
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 NOTCH1 are frequent in HNSCC, and inhibition of PI3K can selectively target NOTCH1 mutant (NOTCH1MUT) HNSCC cells. In this study, we identify several proteins that are differentially regulated in HNSCC cells after PI3K inhibition based on NOTCH1MUT status. Expression of Aurora kinase B (Aurora B), AKT, and PDK1 following PI3K inhibition was significantly lower in NOTCH1MUT cell lines than in wild-type NOTCH1 (NOTCH1WT) cells or NOTCH1MUT cells with acquired resistance to PI3K inhibition. Combined inhibition of PI3K and Aurora B was synergistic, enhancing apoptosis in vitro and leading to durable tumor regression in vivo. Overexpression of Aurora B in NOTCH1MUT HNSCC cells led to resistance to PI3K inhibition, while Aurora B knockdown increased sensitivity of NOTCH1WT cells. In addition, overexpression of Aurora B in NOTCH1MUT HNSCC cells increased total protein levels of AKT and PDK1. AKT depletion in NOTCH1WT cells and overexpression in NOTCH1MUT 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 NOTCH1MUT cells to mediate HNSCC survival in response to PI3K inhibition. These findings may lead to an effective therapeutic approach for HNSCC with NOTCH1MUT while sparing normal cells.
| Original language | English |
|---|---|
| Pages (from-to) | 4444-4456 |
| Number of pages | 13 |
| Journal | Cancer Research |
| Volume | 82 |
| Issue number | 23 |
| DOIs | |
| State | Published - 2 Dec 2022 |
| Externally published | Yes |
Bibliographical note
Publisher Copyright:© 2022 American Association for Cancer Research.
Funding
The authors thank Erica Goodoff in MD Anderson’s Research Medical Library for editing the manuscript. This work was supported by philanthropic contributions to The University of Texas MD Anderson Cancer Center’s Oropharynx Discovery Program (to F.M. Johnson), from the NIH (1R01CA235620, to F.M. Johnson and M.J. Frederick), and the Cancer Prevention and Research Institute of Texas (RP200369 to F.M. Johnson and M.J. Frederick). Flow cytometry and bioinformatics analyses were supported by the NCI through MD Anderson’s Cancer Center Support Grant (P30CA016672). F.M. Johnson reports a patent for UTSC.P1483US.CP1 pending to MD Anderson Cancer Center, and F.M. Johnson has received research funding from Takeda and Viracta Therapeutics within the last 36 months. No disclosures were reported by the other authors.
| Funders | Funder number |
|---|---|
| Viracta Therapeutics | |
| National Institutes of Health | |
| National Cancer Institute | P30CA016672, R01CA235620 |
| Cancer Prevention and Research Institute of Texas | RP200369 |
| Takeda Pharmaceutical Company |
