ATPS-852-HYDROXYGLUTARATE DEPLETION IS NOT SUFFICIENT TO INHIBIT GROWTH OF SEVERAL PROGRESSIVE IDH1 MUTANT SOLID CANCER TYPES

Abstract

Targeted agents that inhibit 2-hydroxyglutarate (2-HG) production by mutant IDH1 have shown considerable promise in acute leukemia. To examine the potential effects of 2-HG reduction in IDH1 mutant solid cancers, we treated endogenous IDH1 mutant tumor cells from several tissue types with a well-characterized inhibitor of IDH1 R132H and R132C (IDH1i) in vitro and in vivo. We confirmed potent inhibition of 2-HG formation in vitro in IDH1R132H glioma tumorsphere lines and a fibrosarcoma line, HT1080 (IDH1R132C). Then, we broadly tested 8 endogenous IDH1 mutant cell lines, including 6 IDH1R132H gliomas, HT1080 and a melanoma line E232-2010 (IDH1R132C). IDH1i markedly reduced 2-HG, however did not inhibit in vitro growth of any cell line. We then assessed the effect of IDH1i treatment on mice bearing patient-derived, endogenous IDH1 mutant glioma orthotopic xenografts. Continuous daily oral administration of IDH1i (200 mg BID) achieved marked 2-HG reduction within the tumor. However, we found no significant difference in tumor size or survival of IDH1i-treated versus vehicle-treated mice. Furthermore, neither short-term nor prolonged (>6mo) in vitro IDH1i exposure significantly altered the global trimethylation or dimethylation of histone 3 lysine 9 (H3K9), global trimethylation of H3K27, genomewide distribution of DNA methylation or methylation of the O-6-methylguanine-DNA methyltransferase gene promoter. Paradoxically, long-term in vitro IDH1i incubation resulted in acceleration of cell proliferation and significantly shorter animal survival upon subsequent intracerebral implantation, compared to passage-matched IDH1 mutant glioma cells grown in the absence of IDH1i. Thus, 2-HG levels can be uncoupled from cell proliferation in several IDH1 mutant solid cancer types, and the epigenetic alterations induced by mutant IDH1 are not reversed solely by depletion of 2-HG, even after many cell divisions. Alternative combination therapeutic strategies may be needed for successful growth inhibition of progressive mutant IDH1 solid cancers.