Dual molecular therapy targeting tumor cell heterogeneity improves therapeutic efficacy in glioblastoma.

The intratumoral heterogeneity of glioblastoma, comprising glioblastoma stem cells (GSCs) and differentiated glioblastoma cells (DGCs), contributes to treatment resistance. We explored combination therapy targeting both GSCs and DGCs. Candidate drugs predicted to be highly effective against GSCs and DGCs were identified through in silico screening, which utilized antitumor efficacy data of therapeutic agents and gene expression profiles of cancer cell lines. IC50 values of the candidate drugs were determined using in vitro cell proliferation assays. Belinostat and Dasatinib were found to be the most effective against GSCs and DGCs, respectively. Their combination showed synergistic effects in vitro. Transcriptome analysis revealed the suppression of the G2/M transition and the PI3K-Akt-mTOR signaling pathway following combination therapy. Histological analysis confirmed reduced proliferation and increased apoptosis. In silico screening successfully identified candidate drugs for GSCs and DGCs. These results suggest that the dual targeting of GSCs and DGCs may help overcome intratumoral heterogeneity in glioblastoma.