Onvansertib and Emerging Cancer Treatment Strategies

Cancer treatment has evolved with targeted therapies that disrupt specific molecular pathways driving tumor growth. Traditional chemotherapy affects both healthy and cancerous cells, causing significant side effects. In contrast, precision medicine enhances efficacy while minimizing harm to normal tissues.

A promising strategy involves targeting key regulators of cell division, essential for cancer progression. Onvansertib, a small-molecule inhibitor, has shown potential, particularly in combination with other drugs. Understanding its role in emerging treatments provides insight into combating resistant tumors more effectively.

Molecular Composition And Target

Onvansertib is a selective small-molecule inhibitor targeting Polo-like kinase 1 (PLK1), a serine/threonine kinase central to mitotic progression. It belongs to the class of ATP-competitive inhibitors, binding with high affinity to the ATP-binding pocket of PLK1. This specificity minimizes off-target effects on other Polo-like kinases such as PLK2 and PLK3. PLK1 is frequently overexpressed in malignancies like colorectal, pancreatic, and triple-negative breast cancers, where it drives uncontrolled proliferation.

PLK1 orchestrates multiple mitotic stages, including centrosome maturation, spindle assembly, and chromosome segregation. Cancer cells, which often exhibit dysregulated mitotic control, become highly reliant on PLK1 for survival, making it an attractive target. Elevated PLK1 expression correlates with poor prognosis, reinforcing its role in oncogenesis. By inhibiting PLK1, Onvansertib disrupts mitosis, leading to arrest and apoptosis in cancer cells. This mechanism is particularly beneficial in tumors resistant to conventional therapies, as PLK1 inhibition circumvents alternative survival pathways.

Preclinical and clinical studies validate Onvansertib’s efficacy in PLK1-dependent tumors. In vitro research shows reduced cancer cell viability in acute myeloid leukemia (AML) and metastatic colorectal cancer (mCRC), both exhibiting heightened PLK1 activity. Pharmacokinetic analyses indicate favorable bioavailability and metabolic stability, enabling sustained PLK1 inhibition at therapeutic doses. These properties enhance its potential in combination therapies to improve patient outcomes.

Mechanism Of Action In Cell Division

Onvansertib disrupts mitosis by inhibiting PLK1, a key regulator of cell division. PLK1 facilitates centrosome maturation, spindle assembly, and chromosome segregation. By binding to PLK1’s ATP-binding pocket, Onvansertib prevents its kinase activity, leading to mitotic defects. Centrosomes fail to mature properly, impairing bipolar spindle formation. This triggers the spindle assembly checkpoint (SAC), which halts the cell cycle to prevent chromosome missegregation. Prolonged SAC activation forces cancer cells into mitotic arrest, ultimately leading to apoptosis.

Persistent mitotic arrest induces stress responses culminating in programmed cell death. Cells with misaligned chromosomes experience prolonged activation of checkpoint proteins such as BubR1 and Mad2, preventing anaphase onset. Sustained checkpoint activation depletes energy reserves and generates proteotoxic stress from accumulated misfolded proteins. In response, pro-apoptotic factors like BAX and caspase-3 become activated, driving apoptosis. Live-cell imaging and flow cytometry confirm increased apoptotic markers in Onvansertib-treated cancer cells.

Beyond mitotic arrest, PLK1 inhibition influences genomic stability and tumor progression. Cancer cells rely on PLK1 to recover from replication stress and DNA damage incurred during rapid proliferation. Onvansertib exacerbates genomic instability, leading to chromosomal aberrations and mitotic failure. This effect is particularly significant in tumors with pre-existing DNA repair defects, as these cells struggle to manage mitotic errors. Research shows PLK1 inhibition enhances the efficacy of genotoxic agents by preventing cancer cells from escaping mitotic failure.

Interaction With PARP Inhibitors

Onvansertib’s therapeutic potential expands when combined with poly (ADP-ribose) polymerase (PARP) inhibitors, which target DNA repair mechanisms. PARP enzymes detect and repair single-strand DNA breaks. Inhibition prevents lesion repair, leading to replication fork collapse and double-strand breaks. Tumors with homologous recombination repair (HRR) deficiencies, such as BRCA1/2-mutated cancers, are particularly vulnerable to PARP inhibitors. Onvansertib compounds this weakness by further destabilizing mitotic integrity, making it harder for cancer cells to maintain genomic stability.

Preclinical studies show PLK1 inhibition enhances PARP inhibitors’ cytotoxic effects by disrupting mitotic recovery after DNA damage. Tumor cells exposed to Onvansertib and PARP inhibitors, such as olaparib or rucaparib, experience prolonged mitotic arrest and increased chromosomal fragmentation. This synergy arises from the inability to resolve replication stress when both repair pathways are compromised. In BRCA-mutated ovarian and triple-negative breast cancer models, dual therapy significantly increases apoptosis compared to either agent alone. The combination prevents adaptive mechanisms that restore DNA repair capacity, making it effective even in PARP inhibitor-resistant cancers.

Early clinical trials are evaluating the safety and efficacy of this combination in advanced malignancies. Preliminary findings suggest improved progression-free survival in recurrent ovarian and prostate cancers, particularly in HRR-deficient patients. However, tolerability remains a focus, as both agents influence cell cycle progression and genomic maintenance. Observed adverse effects include hematologic toxicities such as neutropenia and thrombocytopenia, necessitating dose optimization. Despite these challenges, the rationale for combining Onvansertib with PARP inhibitors remains strong, leveraging synthetic lethality to drive cancer cells into an unrecoverable state of genomic instability.