Cancer cells depend on lengthening their telomeres, usually via telomerase activity. Telomeres are the caps of repeated DNA sequences at the ends of chromosomes. A little length is lost with each cell division, and when short a cell either self-destructs or becomes senescent and ceases replication. Cancer cells can only replicate continually if telomeres are extended continually. Thus some research groups are looking into sabotage of telomerase or the alternative lengthening of telomeres (ALT) processes as the basis for a truly universal cancer therapy. Others, as here, are investigating ways to interfere in mechanisms that protect telomeres from degradation, hopefully obtaining much the same result in the end.
In the context of tumorigenesis, telomere shortening is associated with apparent antagonistic outcomes: on one side, it favors cancer initiation through mechanisms involving genome instability, while on the other side, it prevents cancer progression, due to the activation of the DNA damage response (DDR) checkpoint behaving as a cell-intrinsic proliferation barrier. Consequently, telomerase, which can compensate for replicative erosion by adding telomeric DNA repeats at the chromosomal DNA extremities, is crucial for cancer progression and is upregulated in nearly 90% of human cancers.
In human cells, telomeric chromatin is organized into a terminal loop (t-loop), nucleosomes, the non-coding RNA TERRA, the protein complex shelterin, and a network of nuclear factors. The shelterin complex is essential for telomere protection and comprises six subunits: Three subunits bind telomeric DNA (TRF1, TRF2, and POT1), while the three others establish protein-protein contacts: RAP1 with TRF2, TIN2 with TRF1, TRF2, and TPP1 with TIN2 and POT1. Each shelterin subunit has a specific role in telomere protection, i.e., TRF1 prevents replication stress, TRF2 blocks ataxia telangiectasia-mutated (ATM) signaling and non-homologous end joining (NHEJ), while POT1 blocks ataxia telangiectasia and Rad3-related (ATR) signaling.
A wealth of recent findings points toward shelterin as a valuable alternative to telomerase to fight cancer. Researchers have identified small molecule compounds targeting TRF1 using an FDA-approved library to screen for TRF1 expression and localization. Several of the drugs downregulating TRF1 expression interfere with common cancer signaling pathways. Treatment of lung cancer and glioblastoma cells with these compounds triggered DDR activation at telomeres and telomere replication defects. In patient-derived glioblastoma stem cells (GSC), these TRF1 inhibitors reduced stemness in vitro.