Abstract
Most tumors circumvent telomere-length imposed replicative limits through expression of telomerase, the reverse transcriptase that maintains telomere length. Substantial evidence that AKT activity is required for telomerase activity exists, indicating that AKT inhibitors may also function as telomerase inhibitors. This possibility has not been investigated in a clinical context despite many clinical trials evaluating AKT inhibitors. We tested if Perifosine, an AKT inhibitor in clinical trials, inhibits telomerase activity and telomere maintenance in tissue culture and orthotopic xenograft models as well as in purified CLL samples from a phase II Perifosine clinical trial. We demonstrate that Perifosine inhibits telomerase activity and induces telomere shortening in a wide variety of cell lines in vitro, though there is substantial heterogeneity in long-term responses to Perifosine between cell lines. Perifosine did reduce primary breast cancer orthotopic xenograft tumor size, but did not impact metastatic burden in a statistically significant manner. However, Perifosine reduced telomerase activity in four of six CLL patients evaluated. Two of the patients were treated for four to six months and shortening of the shortest telomeres occurred in both patients' cells. These results indicate that it may be possible to repurpose Perifosine or other AKT pathway inhibitors as a novel approach to targeting telomerase.
Highlights
The ends of chromosomes are protected from recognition as double strand DNA breaks by telomeres, nucleoprotein structures on the ends of the chromosomes which consist of telomeric TTAGGG repeats and telomere-binding proteins known collectively as the Shelterin complex (TRF1, TRF2, TIN2, TPP1, POT1 and Rap1) [1]
In vitro effects of perifosine on telomerase activity and telomere length To evaluate the effects of Perifosine on telomere length and telomerase activity, we cultured a panel of cell lines exposed to clinically relevant Perifosine concentrations for extended periods of time
This work has shown that Perifosine, an AKT inhibitor, can prevent telomere maintenance in vitro, in xenograft models and in CLL patients continuously treated with Perifosine
Summary
The ends of chromosomes are protected from recognition as double strand DNA breaks by telomeres, nucleoprotein structures on the ends of the chromosomes which consist of telomeric TTAGGG repeats and telomere-binding proteins known collectively as the Shelterin complex (TRF1, TRF2, TIN2, TPP1, POT1 and Rap1) [1]. When telomeres become sufficiently short, an unrepairable DNA damage signal initiates a p53/p21-mediated growth arrest [3] This process is partially prevented in the germ line and certain proliferative stem cell compartments by telomerase, a ribonucleoprotein reverse transcriptase that uses its RNA component, hTR/hTERC, to template the addition of new telomere repeats onto the ends of the telomeres. Activation of telomerase is one of the most common perturbations observed in malignancy, present in roughly 90% of tumors [5] Given this high rate of activation in tumors, low redundancy in telomere maintenance mechanisms and the absence of telomerase activity in most somatic cell compartments, telomerase inhibitors could be effective against a broad spectrum of tumors www.impactjournals.com/oncotarget with minimal effects on most normal tissues. Recent setbacks in the clinical trajectories of telomerase inhibitors [7] underscore the need for new strategies for telomerase inhibition
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