Efficacy of Polo-life kinase 1 inhibitors in preclinical models of small cell lung cancer

Small cell lung cancer (SCLC) remains a significant health problem with more than 180,000 newly afflicted patients worldwide per year. Recurrence following initial frontline therapy is associated with resistance to salvage treatment and remains the area of greatest unmet need for SCLC patients. This study systematically examined the efficacy of three different polo like kinase 1 (PLK1) inhibitors in preclinical models of SCLC. The study uncovered robust in vitro activity of PLK1 inhibitors against SCLC cell lines and confirmed the efficacy in patient-derived xenograft models of platinum sensitive and resistant SCLC. A known challenge of targeted therapies in the clinic is the inevitable development of resistance and loss of efficacy. Therefore, understanding the potential mechanisms driving acquired resistance could offer additional strategies to enhance efficacy, delay the development of resistance or reverse the resistance. We generated lab-derived resistant SCLC cells by continuous exposure of parental cells to increasing concentration of onvansertib and performed RNA-seq to identify potential resistance mechanisms. Overall design: To develop onvansertib-resistant SCLC H526 cells, H526 cells were grown with increasing onvansertib concentrations (10 nM up to 75 nM) over a one year period. Total RNA was isolated and submitted for RNA-seq.