Synthetic lethality describes a cancer specific dependency on a particular gene product . By definition normal cells do not have this dependency, which is generated by the cancer’s altered genetic background, so loss of the synthetic lethal gene product has limited toxic effect. Finding synthetic lethality is very attractive as drugs that target them are specific to the cancer, limiting side effects that are generally associated with chemotherapy. Polo-Like Kinase 1 (PLK1) may prove to be a widely applicable drug target that exploits synthetic lethality for cancer therapy.
The kinase activity of PLK1 activates the anaphase-promoting complex (APC/C) ubiquitin ligase activity that is required for degradation of mitotic cyclins, facilitation of sister chromatid segregation, and initiation of mitotic exit in both normal and diseased tissues. Causaly’s knowledge engine found 22 lines of evidence in 9 papers that directly link PLK1 protein with APC/C. PLK1 is often upregulated or and/or constitutively active in cancers. Causaly’s engine found a further 20 papers linking PLK1 protein to tumour growth. There were a combined 27 lines of evidence for PLK1 protein as a prognostic marker in oesophageal and gastric cancer.
A synthetic lethal screen of colon cancer cell lines with KRAS activating mutations revealed PLK1 as a synthetic lethal combination . This is significant as KRAS mutation is common in other gastrointestinal cancers as well, as high as 90% of pancreatic cancers. Indeed, an inhibitor of PLK1 has been found to inhibit the proliferation of pancreatic cancer cell lines and ultimately induce apoptosis .
The Causaly engine found evidence that the FDA approved drug dasatinib (Sprycel) for Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia is an effective inhibitor of PLK1. Evidence shows that the FDA approved proteasome inhibitor bortezomib (Velcade) for multiple myeloma and mantle cell lymphoma can reduce PLK1 protein levels.
Interestingly the Causaly engine also found evidence that the FDA approved anti-alcohol abuse drug Disulfiram inhibited PLK1 expression in cell lines and could be investigated as a candidate for anti-cancer repurposing .
The FDA approved non-selective histone deacetylase inhibitor panobinostat (Farydak) for relapsed or relapsed and refractory multiple myeloma also causes a loss of PLK1 protein in cells. FDA approved Epidermal growth factor receptor (EGFR) inhibitor dacomitinib (Vizimpro) for non-small-cell lung carcinoma (NSCLC) that has metastasized and has EGFR mutation including Exon 19 deletion or the L858R substitution in exon 21 was also found to inhibit PLK1.
Multiple PLK1 inhibitors are in clinical trials including blood and solid cancers . Causaly found at least 14 investigational drugs under development (INDs), including genistein, an isoflavone that was first isolated in 1899. In addition, Wortmannin was pinpointed, and although this preclinically promising drug was abandoned in the clinic, it could be revived as an IND candidate by reformulation using nanoparticles. 
Bufalin a component of Chinese traditional medicine derived from toad venom was also identified. Toad venom extract has been investigated in cancer clinical trials but failed to deliver efficacy. A more soluble formulation of bufalin is currently under development. Preclinical evidence exists that casticin, a methyoxylated flavonol found in some plants used in traditional Chinese medicine, reduces the protein levels of PLK1. Causaly also found evidence that nutgall and oak bark extract, purpurogallin, decreased centrosomal and kinetochore localization of PLK1, but no clinical trials have been carried out. Evidence for the ability of poloxin to inhibit PLK1 was identified, but this drug is not currently in any clinical trials.
Due diligence for a new drug development programme, necessitates a thorough understanding of the target, and the drugs, chemicals, or biologics that are already known to medicine. This can be a daunting task as there is no simple set of keywords that will pull out all of the relevant literature, hence the value of expert knowledge.
Experts, however, are not always available, or at a price that might allow an important target exploration on a limited budget. Causaly levels the playing field by acting as the expert, showing target-drug, target-disease relationships in the dendrogram view, and then allowing scientists to dig deeper.
Using this approach rapidly allowed the identification of some promising, but under-explored oncology drug candidates that target PLK1. This is noteworthy as PLK1 drugs have a high potential for use in cancer specific synthetic lethal combinations, producing more effective treatments with fewer toxic side effects.
David is a consultant and medical writer with a focus on biotechnology.
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