Impact of the AurkA Phe31-Ile polymorphism as a predictive marker on the succeptibility of HNSCC patients to Cetuximab therapy

Introduction:

The EGFR antibody cetuximab has significantly increased survival of HNSCC patients, but the individual outcome varies strongly. Overexpression of Aurora Kinases, Ser-Thr Kinases regulating cell cycle, is found in most solid tumors and in 90% of HNSCC. The Aurora Kinase A (AurkA) has a polymorphism with functional significance but a poorly understood mechanism. Here we evaluate the efficacy of anti-EGFR treatment as a function of the AurKA polymorphism in HNSCC cell lines and in primary patient material.

Methods:

The survival and proliferation of AurkA homo- (Cal27) and heterozygous (HN) HNSCC cell lines was evaluated using colony formation and flow cytometric assays and siRNA knockdown of AurkA. Then tumor and normal tissue of 434 patients with HNSCC was analyzed retrospectively. The AurkA and HPV status of the samples were correlated with the overall survival (OS) of the patients stratified in 3 collectives of different therapeutic regimes, one of which received cetuximab.

Results:

In vitro, cell lines homozygous for the polymorphism show significantly decreased survival and less proliferation under cetuximab treatment. This effect presents itself even more clearly in HPV positive cell lines. Kaplan-Meier-Analysis of the OS in all patients treated with cetuximab show significantly better outcome for AurkA homozygous patients. This effect as well correlates closely with a positive HPV-status of the tumor.

Conclusion:

In this study we provide evidence for the predictive value of AurkA polymorphism for the efficacy of Cetuximab treatment. AurkA homozygous HNSCC cells respond well to cetuximab mono-treatment and resistance can be overcome by Aurk knockdown. Patients with Tumors homozygous for AurkA and positive for HPV respond best and show prolonged survival.

Publication History

Publication Date:
23 April 2019 (online)