DDDR-60. Investigating CDK2 and CDK4 Inhibition in IDH-Mutant Glioma with CDKN2A Deletion

Abstract Despite initial responsiveness to therapy, IDH-mutant gliomas frequently recur with aggressive clinical features, often accompanied by genomic alterations such as CDKN2A homozygous deletion. This loss of p16 disrupts CDK-Rb pathway regulation and provides a rationale for CDK-targeted therapy. We have previously demonstrated that CDKN2A-deleted IDH-mutant gliomas are sensitive to a CDK4/6 inhibitor, like Abemaciclib. We hypothesized that selective inhibition of CDK2 and CDK4, alone or in combination, could be an effective targeted therapeutic strategy in these tumors, with potentially reduced toxicity through more selective targeting. To test this, we assessed the response of IDH-mutant glioma cell lines (with and without CDKN2A deletion) to CDK2 inhibitors (INX-315, Tagtociclib), a CDK4 inhibitor (Atirmociclib), and their combination. Broader inhibitors, including Abemaciclib and PF-06873600 (CDK4/6 and CDK2/4/6 inhibitors, respectively), we measured the effect of the drug on cell viability and confirmed the impact of the drug on pathway activity by western blot mediators of CDK-Rb activity. Selective CDK2 or CDK4 inhibition, alone or combined, did not significantly reduce viability across cell lines, regardless of CDKN2A status. In contrast, CDK4/6 inhibition (Abemaciclib) and CDK2/4/6 inhibition (PF-06873600) consistently suppressed viability, particularly in CDKN2A-deleted lines. These results suggest that CDK6 activity, or synergistic inhibition across CDK2/4/6, may be critical for efficacy. The lack of efficacy with selective inhibitors highlights on non-redundant roles of CDK in G1/S checkpoint regulation and underscores the complexity of CDK targeting in glioma.