Improving therapeutic strategies for triple-negative breast cancer: synergistic effects of DKC1 inhibition and paclitaxel.

Abstract

Background: Paclitaxel (PTX) is a standard treatment for triple-negative breast cancer (TNBC), but its effectiveness is often compromised by toxicity at therapeutic doses. Dyskerin pseudouridine synthase 1 (DKC1), a telomerase subunit, is overexpressed in TNBC and associated with poor prognosis. This study investigates whether combining PTX with R1D2-10, a novel DKC1 inhibitor developed by our group, enhances cytotoxicity while reducing required PTX dosages.

Research design and methods: In vitro assays were conducted using MDA-MB-231 and MDA-MB-468 TNBC cell lines, treated with R1D2-10, PTX or their combination. Cytotoxicity, drug synergy, clonogenic capacity, cell cycle distribution, apoptosis, and DNA damage markers were evaluated to assess efficacy and mechanism of action.

Results: The combination demonstrated synergistic effects, showing dose-dependent cytotoxicity and achieving a Dose Reduction Index (DRI) exceeding 3. Furthermore, the treatment significantly reduced colony formation and induced a rise in cell cycle population, both at the G2/M and Sub-G1 phases. These effects are supported by increased apoptosis and gene expression markers for cell cycle arrest, without evidence of replication stress or DNA damage.

Conclusions: Combining R1D2-10 with PTX may provide an effective therapeutic strategy to reduce dose-related toxicity while enhancing chemotherapy effects in TNBC. Further, in vivo studies are needed to validate these findings.