Differential Response to Ferroptosis Inducers in Low Grade Glioma Murine Cell Lines

Introduction: Gliomas remain the most common and aggressive brain tumors in adult patients. Low grade gliomas (LGGs) are defined by their mutant isocitrate dehydrogenase (IDH) and have a relatively favorable prognosis compared to their higher grade counterparts. However, LGGs often progress to higher grades and become fatal despite treatment. Recent studies have shown that low grade gliomas are particularly sensitive to ferroptosis. RSL3, IKE, Sulfasalazine, and Sorafenib have all been noted to induce ferroptosis in glioma cells. However, how IDH mutant LGGs respond to these ferroptosis inducers remains to be observed.

Methods: Mouse glioma cells that express IDH1 wild-type or IDH1 R132H were serially transplanted into immune-competent mice to produce the C266-6 (wild-type) and C266-2 (IDH1 mutant) cell lines. Afterwards, cell viability between the two cell lines were compared when treated with RSL3, IKE, Sulfasalazine, and Sorafenib.

Results: We show that mutant IDH1 LGGs confer resistance to cell death from ferroptosis induction with treatments of RSL3 compared to wild-type. Moreover, mutant IDH1 LGGs show resistance to cell death from IKE at lower concentrations. Both wild-type and IDH1 mutant cells respond similarly to sulfasalazine and sorafenib.

Conclusion : Our findings show that the IDH1 R132H mutation can promote glioma tumor cell survival when under stress by ferroptotic inducing compounds. Moreover, IDH1 R132H mutant cells are resistant to RSL3 induced cell death but are sensitive to IKE, Sulfasalazine, and Sorafenib. RSL3 functions downstream to inhibit GPX4. Alternatively, IKE, Sulfasalazine, and Sorafenib function upstream and instead inhibit system xc-. The effects seen with the system xc- inhibitors suggest that upstream ferroptosis targets in IDH1 R132H LGGs may have less of a differential response compared to downstream targets.