Cyclacel Pharmaceuticals has highlighted promising preclinical research demonstrating that biliary tract cancer cells are sensitive to plogosertib, the company's PLK1 inhibitor currently in clinical development. The independent study, published in Cancer Research and previously presented at the American Association of Cancer Research 2025 annual meeting, reveals potential new treatment avenues for this aggressive malignancy.
Preclinical Efficacy and Mechanism of Action
The research, titled "Evaluation of antitumor effects of plogosertib, PLK1 inhibitor in biliary tract cancer with BUBR1 as a potential biomarker," found that several biliary tract cancer (BTC) cell lines were sensitive to plogosertib both as monotherapy and in combination treatments. Consistent with its antimitotic mechanism of action, plogosertib promoted mitotic checkpoint complex formation in prometaphase, which induced mitotic arrest resulting in apoptosis of BTC cells.
The investigators identified BUBR1, a critical mitotic checkpoint protein, as a potential biomarker to assess plogosertib's effectiveness. BTC cells with high BUBR1 expression demonstrated greater sensitivity to plogosertib compared to those with low expression levels.
Combination Therapy Potential
The study concluded that BTC cells with high BUBR1 expression are sensitive to the PLK1 inhibitor and demonstrate synergistic effects when combined with an ATR inhibitor. This suggests that targeting PLK1 could be an effective strategy for BTC treatment, with BUBR1 expression serving as a potential biomarker to inform optimal combination therapies.
Addressing Critical Medical Need
Biliary tract cancer, also called cholangiocarcinoma, is a rare but aggressive cancer occurring in the biliary tract, a network of small tubes connecting the liver, gallbladder and small intestine. According to estimates from the National Cancer Institute's SEER database, the annual US incidence of BTC is 4.4 per 100,000. The prognosis for BTC patients remains poor, with 5-year overall survival of approximately 10-40% even after surgical tumor resection.
Current BTC treatment strategies include chemotherapy, surgery, radiation and targeted medicines depending on location and stage. However, as these approaches are not curative, there is an urgent, unmet medical need to treat patients with relapsed, refractory and/or unresectable BTC.
PLK1 Inhibition Strategy
Polo-like kinase 1 (PLK1) is a serine/threonine kinase that plays a central role in cell division or mitosis. PLK1 serves as an important regulator of the DNA damage cell cycle checkpoint, mitotic entry and exit, spindle formation and cytokinesis. Cancer cells, particularly KRAS mutated and p53(-) cells, are very sensitive to PLK1 depletion, while normal cells with intact cell cycle checkpoints are less sensitive.
Plogosertib (formerly CYC140) is a novel, small molecule, selective and potent PLK1 inhibitor that has demonstrated impressive efficacy in human tumor xenografts at nontoxic doses. PLK1 overexpression correlates with poor patient prognosis in several tumors, including biliary tract, esophageal, fibrolamellar liver, gastric, leukemia, lung, ovarian, and squamous cell cancers, as well as MYC-amplified cancers.
Clinical Development Progress
Initial dose escalation data from a Phase 1 clinical study of oral plogosertib suggest that the compound is well tolerated with no dose limiting toxicity observed in five dosing schedules. Clinical benefit was observed in patients with adenoid cystic, biliary tract, ovarian, and squamous cell sinus cancers.
Cyclacel's translational biology program supports the development of plogosertib in solid tumors and leukemias. Preclinical data from independent groups have shown that certain ARID1A- and/or SMARCA-mutated cancers, and cancers associated with DNAJ-PKAc fusions, may benefit from treatment with plogosertib. Additionally, recent data suggest that PLK1 inhibition may be effective in KRAS-mutated metastatic colorectal cancer.
