The Clinical Kinase Index: A Method to Prioritize Understudied Kinases as Drug Targets for the Treatment of Cancer

Abstract

Summary The approval of the first kinase inhibitor, Gleevec, ushered in a paradigm shift for oncological treatment—the use of genomic data for targeted, efficacious therapies. Since then, over 48 additional small-molecule kinase inhibitors have been approved, solidifying the case for kinases as a highly druggable and attractive target class. Despite the role deregulated kinase activity plays in cancer, only 8% of the kinome has been effectively “drugged.” Moreover, 24% of the 634 human kinases are understudied. We have developed a comprehensive scoring system that utilizes differential gene expression, pathological parameters, overall survival, and mutational hotspot analysis to rank and prioritize clinically relevant kinases across 17 solid tumor cancers from The Cancer Genome Atlas. We have developed the clinical kinase index (CKI) app ( http://cki.ccs.miami.edu ) to facilitate interactive analysis of all kinases in each cancer. Collectively, we report that understudied kinases have potential clinical value as biomarkers or drug targets that warrant further study.

Pan-Cancer Analysis of Human Kinome Gene Expression and Promoter DNA Methylation Identifies Dark Kinase Biomarkers in Multiple Cancers

“…Survival analysis also showed overexpression of PKMYT1 leads to lower overall survival in ACC, BLCA, KICH, KIRC, KIRP, LGG, and LUAD cancer types ( Figure 5 b). Other computational studies have also identified PKMYT1 as a prognostic marker in kidney cancer cohorts [ 11 ]. Besides, we identified that hypermethylation of the CpG probe, cg02510853 leads to lower overall survival in KIRC patients ( Figure 5 a and Figure 6 ).…”

“…This also includes the pseudokinase families, which are usually overlooked despite their links to many cancers, which can be attributed to the lack of small molecule inhibitors and assays to evaluate their mechanisms of action [ 6 , 10 ]. As of 2019, only 8% of FDA-approved small molecule inhibitors target kinases, most (70%) of which belong to the Tyr kinase family [ 11 ]. While significant kinase research has been focused on Tyr and Ser/Thr kinases, those belonging to other families have often been understudied, with very little information available on their role in cellular processes and their use as druggable targets.…”

“…Based on an initial study by the National Institutes of Health (NIH), 134 protein kinases are classified as ‘under-studied’ or ‘dark kinases’ based on Jenson PubMed and RO1/PubTator score. Most of these dark kinases belong to the ‘other’, CMGC, Ca 2+ /calmodulin-dependent protein kinase (CaMK) groups [ 11 , 12 ]. Data resources such as the dark kinase knowledgebase (DKK), supported through NIH’s Illuminating the Druggable Genome (IDG) program, collates both experimental and bioinformatic data to encourage the study of understudied kinases [ 13 , 14 ].…”

Innovations and Patent Trends in the Development of USFDA Approved Protein Kinase Inhibitors in the Last Two Decades

“…Even though CAMK, CK1, or AGC kinases groups are well-known and evidenced as the primary targets for cancer, there are no investigational drugs that target these kinases are enrolled. So far only 8% of the entire kinome has been effectively “drugged” and a quarter of human kinases are vastly understudied [ 19 ]. A wide-ranging scoring system to rank and prioritize clinically relevant kinase targets of different solid tumor cancers from The Cancer Genome Atlas (TCGA) has been developed [ 19 ].…”

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