DDDR-07. Overcoming Therapeutic Resistance in IDH1 Mutant Glioma via Synthetic Lethality-Based Combination Therapy

Abstract Isocitrate dehydrogenase 1 (IDH1) mutant gliomas are typically diagnosed as low-grade tumors with relatively slow progression. However, many of these tumors inevitably undergo malignant transformation, becoming highly aggressive and resistant to current therapies. While small-molecule inhibitors targeting mutant IDH1 have shown clinical efficacy in some low-grade gliomas, their therapeutic impact in high-grade gliomas remains suboptimal, underscoring the need for new treatment strategies. In this study, we sought to identify novel vulnerabilities in IDH1 mutant gliomas that could be exploited to overcome resistance to mutant IDH1 inhibitors. We conducted a genome-wide CRISPR/Cas9 knockout screening in IDH1 mutant glioma cell lines treated with a mutant IDH1 inhibitor. This approach uncovered multiple candidate genes whose loss induced synthetic lethality in the presence of IDH1 inhibition, particularly genes involved in cell cycle regulation and survival signaling. Although monotherapy with the IDH1 inhibitor successfully reduced intracellular D-2-hydroxyglutarate levels, it exhibited only limited effects on cell proliferation. In contrast, combination treatment with the IDH1 inhibitor and small-molecule inhibitors targeting selected synthetic lethal genes led to marked synergistic antitumor effects, including robust induction of apoptosis. These results were consistently observed in two independent IDH1 mutant glioma cell lines, suggesting potential generalizability of the strategy. We are currently investigating the underlying molecular mechanisms driving this synergy, including changes in epigenetic landscapes and chromatin accessibility, to better understand the biological consequences of combination therapy. Our findings propose a promising therapeutic strategy that targets the adaptive resistance mechanisms of IDH1 mutant gliomas through synthetic lethality. This approach may pave the way for precision medicine tailored to the specific vulnerabilities of malignant IDH1 mutant gliomas and provide new avenues to improve outcomes for patients with treatment-refractory disease.