Abstract 1329: Combination treatment with CB-839 and romidepsin induces apoptosis and suppresses cell viability in preclinical models of chondrosarcoma

Abstract

Abstract Chondrosarcomas are the second most frequently occurring type of bone malignancy, and account for approximately 25% of all bone sarcomas. They are often highly aggressive neoplasms that rapidly progress and eventually recur and give distant metastases. They are largely considered to be resistant to conventional chemotherapy and radiotherapy. Several studies have reported that mTORC1 stimulates glutamine metabolism and increased mitogenic signaling through activation of the mTORC pathway, coupled with deregulation of the Cyclin D/retinoblastoma (Rb) pathway is a common feature of certain malignancies. In the present study, we hypothesized that concurrent inhibition of glutamine metabolism and histone acetylation could result in decreased viability of chondrosarcoma cells. To test this, we used a panel of chondrosarcoma cell lines including IDH wild type (CH2879), IDH1 mutant (JJ012) and IDH2 mutant (SW1353) cell line. Results from our in vitro proliferation assay showed that combination of sub-IC50 concentrations of the CB-839 (Glutaminase inhibitor) and Romidepsin (HDAC inhibitor) resulted in decreased cell viability of all the three chondrosarcoma cell lines when compared to either of the two drugs alone. Western blot analysis showed induction of cleaved Poly-ADP Ribose Polymerase (PARP) as well as cleaved caspase 3, known markers of apoptosis and down regulation of mTORC1 targets such as phospho-S6 and Phospho-p44/42 MAPK such as ERK1/2. Combination treatment also resulted in increased induction of histone acetylation (AcH3). Cell cycle analysis showed induction of sub-G1 population phase in combination treatment. Previous reports have shown that CpG methylation is a critical event in transcriptional repression of hyper methylated genes in cancer. To this end, we show that combination treatment with CB-839 and Romidepsin results in down regulation of (H3K9) methylation. Taken together, our data strongly suggests that combination treatment with CB-839 (Glutaminase inhibitor) and Romidepsin (HDAC inhibitor) is a novel treatment approach and merits evaluation in the treatment of chondrosarcoma. Citation Format: Tahir N. Sheikh, Parag P. Patwardhan, Gary K. Schwartz. Combination treatment with CB-839 and romidepsin induces apoptosis and suppresses cell viability in preclinical models of chondrosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1329.