This study is, to our knowledge, the first reports about dual PLK1 and BRD4 degraders, which potentially represents an important therapeutic advance in the treatment of cancer.
The observation that Plk1 is overexpressed in multiple human malignancies, including non-small-cell lung cancer (NSCLC), gave rise to the development of several small-molecule inhibitors.
Polo-like kinase 1 (PLK1) has been recognized as a valuable target in cancer treatment due to the prognostic implication of PLK1 in cancer patients and its clinical relevance between the overexpression of PLK1 and the reduced survival rates of several carcinoma patients.
PLK1 is regarded as a potential cancer target, and it is specifically over-expressed in different types of cancer cells, including aforementioned cancers.
Plk1 has strong clinical relevance, as it is considered a bona fide cancer target, it is found overexpressed in a large collection of different cancer types and this tumoral overexpression often correlates with poor patient prognosis.
To evaluate the role of PLK1 as potential cancer target within a combinatorial trial, we induced strong mitotic arrest in ovarian cancer cell lines by synergistically co-targeting microtubules (paclitaxel) and PLK1 (BI6727) followed by pharmaceutical inhibition of the Anaphase-Promoting Complex (APC/C) using proTAME.
The mitotic subtype was more abundant in Black patients (64.1% vs. 33.7%, P=0.002), indicated worse PFS in Black patients (HR=4.1, P=0.044) including the endometrioid histology (HR=6.1, P=0.024) and exhibited race-associated enrichment in cell cycle signaling and pathways in cancer including PLK1 and BIRC7.
We assessed Plk1 expression in five chemoresistant cancer cell types and found that Plk1 and its downstream phosphatase Cdc25c were selectively overexpressed in tamoxifen-resistant MCF-7 (TAMR-MCF-7) breast cancer cells.
It is interesting to note that all six top-ranked genes proposed to be cancer-associated (PLK1, MCM2, MCM3, MCM7, MCM10 and SKP2) were downregulated by MP-HX in both cell lines.
Finally, our data generated from both human cancer cell lines and mouse xenograft model showed that cancer cells carrying the unphosphorylated form of Numb by Plk1 are more sensitive to doxorubicin, a classical chemotherapeutic drug.
KLHLs are thus intriguing genes for cancer as they can directly influence the degradation of therapeutically relevant cell cycle regulators such as Aurora Kinase, PLK1, or CDK1.
Plk1, which regulates the formation of the mitotic spindle, has emerged as a validated drug target for the treatment of cancer, because it is required for numerous types of cancer cells but not for the cell division in noncancer cells.
The results suggest that the soft and small nanoparticles were most efficacious in knocking down polo-like-kinase 1 (PLK1) siRNA, a gene overexpressed in a variety of cancer types.