Identifying Candidate Druggable Targets in Canine Cancer Cell Lines Using Whole-Exome Sequencing

Abstract

Cancer cell culture has been a backbone in cancer research, in which analysis of human cell line mutational profiles often correlates with oncogene addiction and drug sensitivity. We have conducted whole-exome sequence analyses on 33 canine cancer cell lines from 10 cancer types to identify somatic variants that contribute to pathogenesis and therapeutic sensitivity. A total of 66,344 somatic variants were identified. Mutational load ranged from 15.79 to 129.37 per Mb, and 13.2% of variants were located in protein-coding regions (PCR) of 5,085 genes. PCR somatic variants were identified in 232 genes listed in the Cancer Gene Census (COSMIC). Cross-referencing variants with human driving mutations on cBioPortal identified 61 variants as candidate cancer drivers in 30 cell lines. The most frequently mutated cancer driver was TP53 (15 mutations in 12 cell lines). No drivers were identified in three cell lines. We identified 501 non-COSMIC genes with PCR variants that functionally annotate with COSMIC genes. These genes frequently mapped to the KEGG MAPK and PI3K-AKT pathways. We evaluated the cell lines for ERK1/2 and AKT (S473) phosphorylation and sensitivity to the MEK1/2 inhibitor, trametinib. Twelve of the 33 cell lines were trametinibsensitive (IC 50 < 32 nmol/L), all 12 exhibited constitutive or serum-activated ERK1/2 phosphorylation, and 8 carried MAPK pathway cancer driver variants: NF1(2), BRAF(3), N/KRAS(3). This functionally annotated database of canine cell line variants will inform hypothesis-driven preclinical research to support the use of companion animals in clinical trials to test novel combination therapies.

Cross-species oncogenic signatures of breast cancer in canine mammary tumors

“…Although anticancer agents originally developed to treat human cancers may be applied to dogs, little evidence has been given in terms of their therapeutic efficacy, especially in relation to cost effectiveness. Recently, a study of drug sensitivity showed trametinib (a MEK1/2 inhibitor) to be effective in canine cancer cell lines 46 , and we expect more lines of evidence will accumulate on trans-species use of more drugs of these kinds. In spite of a concern regarding the discordance between animal and human in drug efficacy and toxicities 47 , treatment of canine cancer may benefit from the development of novel human cancer drugs that target shared oncogenic mutations (e.g., alpelisib for metastatic breast cancer with PIK3CA mutations 48 ).…”

Cellular processes involved in lung cancer cells exposed to direct current electric field

“…Although the functional enrichment analysis uncovered the link between dcEFs associated genes and cancer-related pathways, however, detail mechanisms were still needed. To further investigate the validity of this link, cBioportal (an online web-based integrated data mining system) was used to explore the genetic alteration of genes associated with lung cancer 24,42,43 . www.nature.com/scientificreports www.nature.com/scientificreports/ Among the six tumor types we used as dataset [44][45][46][47][48][49] , the expression levels of these hub genes varied from 0.2% to 19% (Fig.…”

A domestic cat whole exome sequencing resource for trait discovery

“…WES became recognized as a more efficient means for genome resequencing in 2007 and has increasingly been used to help diagnose patients with rare and genetic diseases 3,4 . By selectively sequencing all protein-coding regions to great depth, WES is a dependable method to find exome variants 5 . Most often WES is a powerful approach to study Mendelian inherited diseases because highly functional impact variants rarely appear in the healthy populations 6 7 .…”