Targeting Aurora A to Overcome Cisplatin Resistance in Head and Neck Cancer

X Li; Z Wang; G G Oakley; L Wang; E A Lanzel; M R Buchakjian; A Peng

doi:10.1177/00220345241309624

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Targeting Aurora A to Overcome Cisplatin Resistance in Head and Neck Cancer

Journal article

Open access

Peer reviewed

Targeting Aurora A to Overcome Cisplatin Resistance in Head and Neck Cancer

X Li, Z Wang, G G Oakley, L Wang, E A Lanzel, M R Buchakjian and A Peng

Journal of dental research, Vol.104(5), pp.531-540

05/2025

DOI: 10.1177/00220345241309624

PMCID: PMC12000625

PMID: 40017056

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Abstract

Cisplatin-based chemotherapy is a cornerstone treatment for advanced recurrent head and neck squamous cell carcinoma (HNSCC). However, the effectiveness of the treatment is often hindered by intrinsic and acquired resistance and associated toxicity, highlighting a pressing unmet clinical need. Here, our compound screening identified Aurora kinase inhibitors, particularly those targeting Aurora A kinase, as potential agents to sensitize resistant HNSCC cells to cisplatin. While Aurora kinases are well-established regulators of mitosis, their precise role in cisplatin resistance is largely unknown, given that cisplatin confers toxicity primarily in cells undergoing DNA replication. We confirmed that depletion of Aurora A or its activators enhanced cisplatin response in resistant HNSCC cells. Analyses of a comprehensive database and locally treated HNSCC patient samples revealed compelling associations between Aurora A overexpression/activation and cisplatin resistance, tumor recurrence, and poor patient survival. Pharmacologic inhibition of Aurora A effectively synergized with cisplatin treatment in cellular assays and a syngeneic mouse tumor model of HNSCC. Mechanistically, Aurora A inhibition enhanced apoptosis induction after cisplatin treatment, particularly in S-phase cells; induced replication stress; and suppressed the repair of cisplatin-induced DNA crosslinking. Taken together, our findings shed light on important functions of Aurora A kinase beyond mitotic regulation. The multifaceted roles of Aurora A suggest its potential as a prime anticancer drug target. Given the ongoing investigations into numerous Aurora inhibitors for cancer therapy, exploring their clinical applications in HNSCC, especially in combination with platinum drugs, may hold significant promise.

DNA damage repair

cancer therapy

tumor recurrence

replication stress

Aurora A kinase

HNSCC

cisplatin

Details

Title: Subtitle: Targeting Aurora A to Overcome Cisplatin Resistance in Head and Neck Cancer
Creators: X Li - University of North Carolina at Chapel Hill
Z Wang - University of Nebraska Medical Center
G G Oakley - University of Nebraska Medical Center
L Wang - University of North Carolina at Chapel Hill
E A Lanzel - University of Iowa
M R Buchakjian - University of Iowa Hospitals and Clinics
A Peng - University of North Carolina at Chapel Hill
Resource Type: Journal article
Publication Details: Journal of dental research, Vol.104(5), pp.531-540
DOI: 10.1177/00220345241309624
PMID: 40017056
PMCID: PMC12000625
NLM abbreviation: J Dent Res
ISSN: 1544-0591
eISSN: 1544-0591
Publisher: SAGE PUBLICATIONS INC
Grant note: National Institutes of Health: CA233037, DE030427
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was funded by the National Institutes of Health (CA233037, DE030427) to A. Peng.
Language: English
Electronic publication date: 02/27/2025
Date published: 05/2025
Academic Unit: Oral Pathology, Radiology and Medicine; Dental Research; Otolaryngology
Record Identifier: 9984793978202771

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