DNA damage response proteins in canine cancer as potential research targets in comparative oncology

Abstract

The DNA damage response (DDR) is a complex signal transduction network that is activated when endogenous or exogenous genotoxins damage or interfere with the replication of genomic DNA. Under such conditions, the DDR promotes DNA repair and ensures accurate replication and division of the genome. High levels of genomic instability are frequently observed in cancers and can stem from germline loss‐of‐function mutations in certain DDR genes, such as BRCA1, BRCA2, and p53, that form the basis of human cancer predisposition syndromes. In addition, mutation and/or aberrant expression of multiple DDR genes are frequently observed in sporadic human cancers. As a result, the DDR is considered to represent a viable target for cancer therapy in humans and a variety of strategies are under investigation. Cancer is also a significant cause of mortality in dogs, a species that offers certain advantages for experimental oncology. Domestic dogs present numerous inbred lines, many of which display predisposition to specific forms of cancer and the study of which may provide insight into the biological basis of this susceptibility. In addition, clinical trials are possible in dogs and may lead to therapeutic insights that could ultimately be extended to humans. Here we review what is known specifically about the DDR in dogs and discuss how this knowledge could be extended and exploited to advance experimental oncology in this species.

Stereotactic radiotherapy (10 Gy X 3) for canine nonlymphomatous intranasal tumors is associated with prolonged survival and minimal risk of severe radiotoxicity

“…One example might be use of radiosensitizers, such as platinum chemotherapeutics, or novel DNA damage response inhibitors. 26 In summary, this 3-fraction SRT protocol is associated with a low risk for quality-of-life-limiting severe acute radiotoxicity, and it is also associated with a risk for late effects (eg, rhinitis, neurologic effects, and fistulas) that is similar to prior reports. Prolonged overall survival is possible even in dogs diagnosed and treated at the end-of-life stage, and our results can be interpreted to suggest that longterm survivorship might be improved through modification of the radiation prescription or use of multimodal combinatorial therapies.…”

Analyses of canine cancer mutations and treatment outcomes using real-world clinico-genomics data of 2119 dogs

“…BRCA1 somatic and germline mutations classified as deleterious and unknown using PROVEAN tools were correlated with better prognosis when treated with dasatinib. Loss-of-function mutations in BRCA1 not only increase the risk of cancer development in humans and dogs but also increase the genomic stability of cells [65][66][67] . BRCA1 is a critical double-strand break repair that utilizes homologous recombination, cell cycle regulation, and protein ubiquitination 68,69 .…”

Studying the DNA damage response pathway in hematopoietic canine cancer cell lines, a necessary step for finding targets to generate new therapies to treat cancer in dogs

“…Basic research analysis studying the role of proteins and cellular responses to different treatments is a first step needed to generate a new therapy to treat cancer or any other disease. The structural and functional properties of the principal components of the DDR system are conserved in mammals, but little is known about them specifically in dogs ( 88 , 89 ). This cellular pathway is under intense investigation in human medicine due to its effects on the clinical aspects of cancer and its potential use in new therapies ( 90 – 93 ).…”