Expanding the Therapeutic Window of PLK1 Inhibition Through hTERT Promoter–Restricted RNA Interference and Reduced-Dose Pharmacotherapy

Abstract Polo-like kinase 1 (PLK1) has long been recognized as a key regulator of mitosis and a potential target in oncology. Early molecular and clinicopathological investigations established its association with proliferation and adverse outcomes in several tumor entities. Subsequent studies demonstrated that antisense oligonucleotides and RNA interference (RNAi) can suppress PLK1 expression, disturb mitotic progression, and increase sensitivity to certain anticancer agents. Yet systemic PLK inhibition remains limited by hematological toxicity, and clinical development of both volasertib and PLK1-directed siRNA has encountered important efficacy and safety constraints. Here, a dual-level therapeutic hypothesis is advanced: expression of a PLK1-targeting artificial microRNA under an hTERT-responsive promoter could preferentially reduce target abundance in selected malignant cells, potentially lowering the systemic exposure to a PLK inhibitor required for antitumor efficacy. This hypothesis does not imply absolute tumor specificity, a change in the biochemical potency of volasertib, or the elimination of bone-marrow toxicity. Its central prediction is an improvement in the tumor-to-normal-tissue therapeutic differential, contingent on functional promoter selectivity, efficient vector delivery, and a favorable relationship between residual PLK1 activity and cellular sensitivity. A staged validation strategy is proposed, with primary hematopoietic progenitors, pharmacodynamic interaction studies, and exposure-matched in vivo comparisons as essential decision points.