Cytokines, JAK-STAT Signaling and Radiation-Induced DNA Repair in Solid Tumors: Novel Opportunities for Radiation Therapy

Abstract

A number of solid tumors are treated with radiation therapy (RT) as a curative modality. At the same time, for certain types of cancers the applicable doses of RT are not high enough to result in a successful eradication of cancer cells. This is often caused by limited pharmacological tools and strategies to selectively sensitize tumors to RT while simultaneously sparing normal tissues from RT. We present an outline of a novel strategy for RT sensitization of solid tumors utilizing Jak inhibitors. Here, recently published pre-clinical data are reviewed which demonstrate the promising role of Jak inhibition in sensitization of tumors to RT. A wide number of currently approved Jak inhibitors for non-malignant conditions are summarized including Jak inhibitors currently in clinical development. Finally, intersection between Jak/Stat and the levels of serum cytokines are presented and discussed as they relate to susceptibility to RT.

Keywords: DNA repair; Jak; Solid tumors; Stat.

Fig. 1.

Overview of repair mechanisms of DNA double-strand breaks (DSDBs). A. Non-homologous end joining repair (NHEJ) is a compact process of re-ligation of the broken DNA ends that requires minimal processing and does not require a template. It occurs throughout the cell cycle. NHEJ is initiated by the binding of the Ku 70–80 heterodimer, one of the subunits of DNA-PK to the double stranded DNA ends to protect it from nuclease digestion. DNA-bound Ku recruits the DNA-protein kinase catalytic subunit (DNA-PKcs), generating the DNA-PK complex which predominantly regulates NHEJ through autophosphorylation and facilitates recruitment of a ligation complex, which encompasses X-ray cross complementing Group 4 (XRCC4) and DNA ligase 4. DNA-PKcs further activate Artemis nuclease which cleave the DNA overhangs. The DNA polymerase λ or μ facilitates the DNA synthesis followed by ligation of the DNA gaps. B. Homologous recombination (HR) DNA repair is a predominantly accurate process that uses a sister chromatid as a template for DSDB repair and functions only in late S/G2 phase. DNA breaks are initially recognized by MRN complex which together with BRCA1and CtIP generates ssDNA overhangs. These overhangs are coated with replication protein A (RPA) which are then exchanged for RAD51 where BRCA1/2 assist the exchange. RAD51 loading promotes invasion onto the undamaged template and strand exchange followed by ligation of the DNA ends. RAD51 paralogues (RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3) assist RAD51 in the HR DNA repair process. The DNA synthesis is performed by polymerase δ or ε.

Fig. 2.

Schematic structure of STAT proteins and their key functional domains. Signal Transducer and Activator of Transcription (STAT) proteins are intracellular transcription factors that regulate various aspects of cellular immunity, proliferation, differentiation and apoptosis. Seven members of STAT family have been identified in mammals: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B) and STAT6. STAT proteins range between 750–900 amino acids and are encoded by different genes. All STAT proteins share conserved structural motifs consisting of an N-terminal domain followed by a coiled-coil, DNA-binding, linker, Src homology 2 (SH2), and a C-terminal transactivation domain. The N-terminal and SH2 domain mediate homologous or heterodimer formation, while the coiled-coil domain functions as a nuclear localization signal (NLS). DNA binding and transcriptional activity are determined by transactivation and DNA binding domains. Y-S within the C-terminal end are the phosphorylation sites for regulation of STAT activation.

Fig. 3.

Canonical JAK-STAT signaling pathway for STAT activation. STAT activation is initiated by the binding of an extracellular ligand to transmembrane receptors which induces the receptors to dimerize bringing receptor associated JAKs to close proximity leading to their activation. The activated JAKs phosphorylate tyrosine residues in the cytoplasmic tails of the receptors that serve as docking sites for cytoplasmic STAT transcription factors recruited to the receptor-JAK protein complex. JAK tyrosine kinases phosphorylate STAT proteins at the C-terminus at specific tyrosine residues leading to nuclear translocation of STAT dimers to regulate the transcription of their target genes.