Selective inhibition of mutant IDH1 by DS-1001b ameliorates aberrant histone modifications and impairs tumor activity in chondrosarcoma

Abstract

Chondrosarcoma is the second most common malignant bone tumor. It is characterized by low vascularity and an abundant extracellular matrix, which confer these tumors resistance to chemotherapy and radiotherapy. There are currently no effective treatment options for relapsed or dedifferentiated chondrosarcoma, and new targeted therapies need to be identified. Isocitrate dehydrogenase (IDH) mutations, which are detected in~50% of chondrosarcoma patients, contribute to malignant transformation by catalyzing the production of 2-hydroxyglutarate (2-HG), a competitive inhibitor of α-ketoglutaratedependent dioxygenases. Mutant IDH inhibitors are therefore potential novel anticancer drugs in IDH mutant tumors. Here, we examined the efficacy of the inhibition of mutant IDH1 as an antitumor approach in chondrosarcoma cells in vitro and in vivo, and investigated the association between the IDH mutation and chondrosarcoma cells. DS-1001b, a novel, orally bioavailable, selective mutant IDH1 inhibitor, impaired the proliferation of chondrosarcoma cells with IDH1 mutations in vitro and in vivo, and decreased 2-HG levels. RNA-seq analysis showed that inhibition of mutant IDH1 promoted chondrocyte differentiation in the conventional chondrosarcoma L835 cell line and caused cell cycle arrest in the dedifferentiated JJ012 cell line. Mutant IDH1-mediated modulation of SOX9 and CDKN1C expression regulated chondrosarcoma tumor progression, and DS-1001b upregulated the expression of these genes via a common mechanism involving the demethylation of H3K9me3. DS-1001b treatment reversed the epigenetic changes caused by aberrant histone modifications. The present data strongly suggest that inhibition of mutant IDH1 is a promising therapeutic approach in chondrosarcoma, particularly for the treatment of relapsed or dedifferentiated chondrosarcoma.

Mutant IDH1 Depletion Downregulates Integrins and Impairs Chondrosarcoma Growth

“…Suijker et al have reported that CpG island methylation and histone H3K4, -9, and -27 trimethylation levels remained unchanged upon specific inhibition of IDH1 mut in chondrosarcoma cells [16]. On the other hand, Nakagawa et al recently demonstrated that selective inhibition of IDH1 mut significantly reduced the levels of H3K4, -9 trimethylation and promotes normal chondrocyte differentiation [40]. This discrepancy suggests that IDH1 mut may promote chondrosarcoma growth through some mechanisms beyond the well-characterized epigenetic effects in other malignancies.…”

SOX9 Knockout Induces Polyploidy and Changes Sensitivity to Tumor Treatment Strategies in a Chondrosarcoma Cell Line

“…This decrease in SOX9 in DDCS in comparison to high-grade chondrosarcoma indicates that SOX9 reduction may support the progression into dedifferentiated stages or could even be a requirement for it. Other in vitro studies recently showed, that tumor progression involved SOX9 and CDKN1C repression in different chondrosarcoma cell lines [ 12 ]. Posttranscriptional regulation of SOX9 via miRs, i.e., miR-145, might be involved in this mechanism as reported by Mak et al [ 16 ].…”

“…One possible explanation for the versatility of SOX9 could be a combination of post-transcriptional modifications, the type of tissue in which it is expressed and certain binding partners. To date, only very few studies have been published on the detailed role of SOX9 during chondrosarcoma development and progression [ 12 ]. The latest studies emphasize the direct crosstalk between SOX9 and a mutation of isocitrate dehydrogenase (IDH) 1.…”

“…The latest studies emphasize the direct crosstalk between SOX9 and a mutation of isocitrate dehydrogenase (IDH) 1. IDH1 mutations are found in ~50% of all chondrosarcoma patients and are involved in malignant transformation [ 12 ]. Thereby, the association between SOX9 and IDH1 highlight the crucial role of SOX9 in chondrosarcoma biology.…”

Discovery of Novel IDH1 Inhibitor Through Comparative Structure-Based Virtual Screening

“…Mutant IDH1 has become a very attractive therapeutic target in the field of antitumor drug discovery, and several pharmaceutical companies have attempted to develop novel small molecule inhibitors against mutant IDH1. So far, several small molecule inhibitors targeting mutant IDH1 enzymes have been developed (see Figure 1) (Rohle et al, 2013;Davis et al, 2014;Deng et al, 2015;Kim et al, 2015;Okoye-Okafor et al, 2015;Law et al, 2016;Chaturvedi et al, 2017;Xie et al, 2017;Popovici-Muller et al, 2018;Nakagawa et al, 2019;Caravella et al, 2020;Konteatis et al, 2020). Some of these have been studied in various preclinical models, and some are currently being evaluated in phase I/II clinical studies for different tumor pathologies with IDH1 enzyme mutations.…”