Ribonucleotide reductase large subunit (RRM1) gene expression predicts efficacy of adjuvant mitotane in adrenocortical cancer
M. Volante1, M. Terzolo1, M. Fassnacht2, I. Rapa1, A. Germano1, S. Sbiera2, F. Daffara1, P. Sperone1, G. Scagliotti1, B. Allolio2, M. Papotti1 & A. Berruti1
Purpose: Mitotane is the reference systemic therapy for adrenocortical carcinoma (ACC), but its mechanism of action and possible predictors of treatment response remain poorly defined. Our aim was to evaluate the gene expression of ribonucleotide reductase large subunit 1 (RRM1) and excision repair cross-complementation group 1 (ERCC1) in ACC as potential biomarkers for clinical outcome and response to mitotane.
Experimental design: Forty-five and 47 tissue samples from two cohorts (Orbassano, Italy; Wurzburg, Germany) of completely resected ACC were centrally analyzed using Real Time PCR for RRM1 and ERCC1 expression. Fifty-four patients received surgery alone and 38 received adjuvant mitotane after surgery. Clinical and pathological features were highly comparable in the two series. H295R and SW-13 ACC cell lines were also used for pharmacological tests.
Results: ERCC1 gene expression was not associated to clinical outcome. In contrast, high RRM1 gene expression was associated to shorter disease-free and overall survival at both univariate and multivariate analysis. In patients with low RRM1 gene expression adjuvant mitotane was associated with improved disease free survival, whereas this effect was lost in cases expressing high RRM1. In vitro mitotane induced strong up-regulation of RRM1 transcription (up to 25-fold increase) in mitotane-insensitive SW-13 cells but not in mitotane-sensitive H295R cells.
Conclusion: Our in vitro and in vivo data indicate that RRM1 gene expression is functionally associated to mitotane sensitivity and represents the first biomarker in ACC predicting response to adjuvant mitotane.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details are unavailable.