TMZ Sensitization in GBM Cell Lines by Sequential Fadraciclib Treatment: An MGMT-Independent Strategy

Current therapies for glioblastoma (GBM) results in a median survival of 15 months, underscoring the need for improved strategies. Since cyclin-dependent kinases (CDKs) regulate the cell cycle and contribute to carcinogenesis, we investigated the CDK2/9 inhibitor, fadraciclib, in combination with temozolomide (TMZ) in tumor spheroid models.

Spheroids from four patient-derived GBM cell lines (GBM03, 06, 14, and 15) were treated with fadraciclib (IC50) and TMZ (10 mM) in mono- and combination therapy in a sequential approach (with TMZ administered following CDK blockade). Viability and cytotoxicity were measured using CellTiter-3D Glo®​ and LDH-Glo™ assays. The Bliss independence index identified the most effective combination for invasion analysis. All four cell lines demonstrated sensitivity to fadraciclib, the methylated GBM06 cell line showed the expected higher sensitivity to TMZ compared to the unmethylated ones. The addition of fadraciclib synergistically enhanced the antitumoral effects, particularly in the unmethylated cell lines. Sequential combination therapy induced a synergistic effect, significantly reducing viability, increasing cytotoxicity, and inhibiting invasion.

Publication History

Article published online:
09 May 2025