Polo-like Kinase 1 Inhibitors and Their Potential Role in Anticancer Therapy, with a Focus on NSCLC

Abstract

Cytotoxic platinum-doublet chemotherapy that includes antimitotic agents is a current standard of care in advanced non-small cell lung cancer (NSCLC). Microtubule-targeting antimitotics, taxanes, and Vinca alkaloids are effective anticancer therapeutics that affect both dividing and nondividing cells. A new generation of antimitotic agents that target regulatory proteins-mitotic kinases and kinesins-has the potential to overcome the limitations related to the role of tubulin in nondividing cells that are associated with traditional antimitotics. This review concentrates on Polo-like kinase 1, a key regulator of mitosis, outlines a rationale for its development as an anticancer target, and discusses data from preclinical and clinical studies of Plk1 inhibitors with a particular focus on NSCLC. Clin Cancer Res; 17(20); 6459-66. Ó2011 AACR. Current Treatment OptionsLung cancer is the second most common malignancy in the United States (219,440 cases) and was the leading cause of cancer-related mortality (159,390 deaths) in 2009 (1). Non-small cell lung cancer (NSCLC) represents 85% of all lung cancers (2); approximately 40% are diagnosed with advanced or metastatic disease (3) with a 5-year survival rate of 14% (4).Chemotherapy with platinum-based doublets (e.g. paclitaxel/carboplatin, docetaxel/cisplatin, gemcitabine/cisplatin, and pemetrexed/cisplatin) is the standard of care in first-line treatment of advanced NSCLC with median overall survival of approximately 8 months (5) and overall response rate of 19% to 30% (5, 6

A Randomized, Open-Label Phase II Trial of Volasertib as Monotherapy and in Combination With Standard-Dose Pemetrexed Compared With Pemetrexed Monotherapy in Second-Line Treatment for Non–Small-Cell Lung Cancer

“…24 However, in this study, the combination of volasertib with pemetrexed did not demonstrate superior clinical efficacy compared with pemetrexed monotherapy. Of interest, the response rate in the combination therapy arm was double that of single-agent pemetrexed, but there was no significant difference in PFS.…”

High Mitotic Activity of Polo-like Kinase 1 Is Required for Chromosome Segregation and Genomic Integrity in Human Epithelial Cells

“…Several Plk1 inhibitors are in clinical development for anticancer therapy (28,29). In clinical studies, mitotic arrest and abnormal spindle structure are classically used to determine whether Plk1 is actually inhibited in vivo.…”

Myotubularin-related Proteins 3 and 4 Interact with Polo-like Kinase 1 and Centrosomal Protein of 55 kDa to Ensure Proper Abscission

“…Defects in abscission, the final step in mitosis, cause aneuploidy that can result in tumorigenesis (64 -66). Both PLK1 and CEP55 have transforming abilities and are overexpressed in a variety of cancers (67)(68)(69)(70), and given the importance of each protein in coordinating abscission, overexpression of either could dramatically accelerate genomic instability. It is possible cells evolved to use MTMR3 and MTMR4 as intermediates linking PLK1 to CEP55 (as opposed to direct binding between CEP55 and the PLK1 polo box domain) as a buffer, ensuring that abscission is not drastically affected by changes in PLK1 activity or CEP55 expression.…”