PO-392 Epigenetic changes in chondrosarcoma caused by IDH mutations as a target for novel anticancer therapy

Abstract

Introduction Chondrosarcoma is the second most common bone malignancy. 50% to 70% of these tumours have a mutation in isocitrate dehydrogenase (IDH)−1 or IDH2, enzymes that are involved in the citric acid cycle. The specific mutations in IDH1/2 lead to the formation of the oncometabolite (D)−2-hydroxyglutarate (D2HG), causing changes in for instance the metabolism and epigenetics of cells. D2HG inhibits α-ketoglutarate (αKG) dependent enzymes such as histone and DNA demethylases, leading to a hypermethylation phenotype. Nowadays, surgery is the only treatment option for these patients which underlines the need for the development of novel therapeutic strategies. We here explore whether the underlying alterations caused by the mutations in IDH1/2 can be used as a target for therapy of unresectable chondrosarcoma. Material and methods To identify targets, we used an epigenetic compound library including 128 inhibitors of epigenetic enzymes such as histone deacetylases (HDACs), histone acetyltransferases (HATs) and DNA methyltransferases (DNMTs). In addition, we performed a siRNA screen focused on 149 genes encoding several epigenetic regulators. The screens were performed in (up to) three chondrosarcoma cell lines to exclude cell line specific effects. JJ012 and SW1353 harbour an IDH1 and IDH2 mutation, respectively, while CH2879 is wildtype for both genes. Furthermore, screens were combined with AGI-5198 (IDH1 mutant inhibitor) or D2HG, to identify synthetic lethal interactions with IDH1/2 mutations. Interesting hits were selected for further study in validation screens and additional chondrosarcoma cell lines. Results and discussions In both screens, no synthetic lethal interactions with IDH1/2 were identified, since there was no significant difference in effectivity of compounds or siRNAs between mutant and wildtype cell lines, and combination with AGI-5198 or D2HG did not rescue or sensitise cells. The epigenetic compound screen identified several interesting compound classes, including PARP, HDAC and DNMT inhibitors. The efficacy of these compounds was confirmed in the other chondrosarcoma cell lines. The epigenetic siRNA screen did not identify single genes with a major effect on cell viability. Conclusion Epigenetic changes in chondrosarcoma seem to be promising therapeutic targets. However, this vulnerability is not correlated with the IDH1/2 mutation status. Further research is needed to explore why these specific compounds inhibit the growth of chondrosarcoma cell lines in vitro and to confirm compound efficacy in vivo.