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.
