Efficacy of plogosertib (CYC149462), a novel orally bioavailable PLK1 inhibitor, on patient-derived models of colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer in adults in the United States. Given the relative rapid cell division in cancer cells compared to most normal cells, drugs targeting mitosis and other cell cycle checkpoints are of interest in CRC treatment. One multi-tasking protein in cell division is polo-like kinase 1 (plk1). Plk1 is a serine threonine kinase that is highly expressed during mitosis and involved in a variety of functions, including spindle assembly, chromosome segregation, G2/M transition, and cytokinesis. Encouragingly, its expression is also significantly higher in CRC compared to normal mucosa, which makes it an attractive cancer-specific target in CRC. In this study, we sought to evaluate the efficacy of plogosertib (CYC149462), a novel plk1 inhibitor, in a series of preclinical models of advanced CRC. Fourteen CRC patient-derived organoids (PDOs) were generated from patients who underwent biopsy or resection for their primary or metastatic CRC under an IRB approved protocol at Duke University. Diagnosis of CRC is confirmed in PDOs using H&E and IHC. Subsequently, PDOs were treated with plogosertib in a range of concentrations from 256pM to 100µM. Drug screens were performed for standard of care agents 5FU, oxaliplatin, and SN38. Viability was assessed with Cell-Titer Glo (CTG) 72 hours after treatment. Using a matched PDX, mice were treated with vehicle or 40 mg/kg daily of plogosertib via oral gavage for 2 weeks, 5 days per week. Cell cycle analysis was performed by flow cytometry, and localization of DNA during mitosis was done by fluorescence staining. CRC PDOs were more sensitive to plogosertib (CYC149462) than 5FU, and oxaliplatin, with significantly lower IC values (518.86±377.47nM for plogosertib vs. 38.87±45.63µM for 5FU, and 37.78±39.61µM for oxaliplatin respectively (ANOVA, P < 0.05). Subsequently, we validated our findings using a matched PDX in which plogosertib treatment led to significant tumor growth inhibition compared to vehicle (t-test, p < 0.05) without serious adverse effects. Furthermore, we showed that plogosertib induces dysfunction in alignment of chromosomes and subsequent G2/M cell cycle arrest (p < 0.05). Together, our study shows that pharmacological inhibition of Plk1 using plogosertib represents a promising therapeutic approach for advanced CRC.

Duke Scholars

Author Shannon Jones McCall Pathology