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 itseffectiveness 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 studyinvestigates 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-468TNBC cell lines, treated with R1D2–10, PTX or their combination. Cytotoxicity, drug synergy, clonogeniccapacity, cell cycle distribution, apoptosis, and DNA damage markers were evaluated to assess efficacyand mechanism of action.Results: The combination demonstrated synergistic effects, showing dose-dependent cytotoxicity andachieving a Dose Reduction Index (DRI) exceeding 3. Furthermore, the treatment significantly reducedcolony 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 reducedose-related toxicity while enhancing chemotherapy effects in TNBC. Further, in vivo studies are needed to validate these findings.