The
DNA-PK
holoenzyme is a fundamental
element of the DNA damage response machinery (DDR), which is responsible for cellular
genomic stability. Consequently, and predictably, over the last decades since its identification and characterization, numerous pre-clinical and clinical studies reported observations correlating aberrant
DNA-PK status and activity with
cancer onset, progression and responses to therapeutic modalities. Notably, various studies have established in recent years the role of
DNA-PK outside the DDR network, corroborating its role as a pleiotropic complex involved in transcriptional programs that operate biologic processes as epithelial to mesenchymal transition (EMT),
hypoxia, metabolism,
nuclear receptors signaling and inflammatory responses. In particular
tumor entities as
prostate cancer, immense research efforts assisted mapping and describing the overall signaling networks regulated by
DNA-PK that control
metastasis and
tumor progression. Correspondingly,
DNA-PK emerges as an obvious therapeutic target in
cancer and data pertaining to various pharmacological approaches have been published, largely in context of combination with
DNA-damaging agents (DDAs) that act by inflicting
DNA double strand breaks (DSBs). Currently, new generation inhibitors are tested in clinical trials. Several excellent reviews have been published in recent years covering the biology of
DNA-PK and its role in
cancer. In the current article we are aiming to systematically describe the main findings on
DNA-PK signaling in major
cancer types, focusing on both preclinical and clinical reports and present a detailed current status of the
DNA-PK inhibitors repertoire.