Targeting the telomere and shelterin complex for cancer therapy: current views and future perspectives

Abstract

Aberrant telomere homeostasis is essential for cell immortality, enabling cells to evade telomere dependent senescence. Disruption of telomere structure and function in cancer cells is highly toxic as shown by detailed pre-clinical evaluation of telomerase inhibitors. Under telomerase inhibition, cells must divide sufficiently frequently to allow one or more telomeres to shorten to an unprotected length. Functioning telomeres are disguised from the DNA damage machinery by DNA remodelling and other activities of the telomere binding complex shelterin. Direct interference with shelterin has been shown to result in cell killing and small molecules directly targeting telomere DNA also have anti-tumour effects partially dependent on shelterin disruption. However, shelterin components have not generally been regarded as therapeutic targets in their own right. In this review, we explore the possibilities for therapeutic targeting of the shelterin complex.

Fig 1

Computational solvent mapping of TRF1/TIN2 interactions. Probes were docked using fast Fourier transform correlation (http://ftmap.bu.edu). (A) shows location of the top ranking cluster in space filling model of TRF1. (B) Orientation of phenol probe adjacent to critical TRF1/TIN2 interacting residues. Stick representation of TIN2 peptide and probe clusters are highlighted in yellow.

Fig 2

Cell based screening for inhibitors of telomere uncapping. (A) Infection with an adenoviral vector expressing mutant hTR (Ad-hTR-mut) induces rapid telom-ere uncapping that can be used as a model system to investigate novel bio-markers or signalling events downstream of telomere dysfunction, or as a screening approach for inhibitors of these pathways. (B) Colorectal carcinoma cell line HCT116 was infected with Ad-hTR-mut. One day after infection cells were drugged with 1.25 μM Suramin or ATM/ATR inhibitor CGK733 (Both Merck, Darmstadt, Germany) or 0.078 μM BIBR1532 (Tocris Bioscience, Ellisville, MO, USA). Five days after infection cell viability was assessed by MTT cytotoxicity assay. Viability of treated cells was expressed as fold of virus alone.