Cancer and Telomeres—An ALTernative to Telomerase

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Science  15 Jun 2012:
Vol. 336, Issue 6087, pp. 1388-1390
DOI: 10.1126/science.1222394

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To grow indefinitely, human cancer cells must counteract the progressive loss of telomeric DNA that universally accompanies cell division. To do this, about 85 to 90% of cancers use telomerase (13), an enzyme that synthesizes the tandem 5′-TTAGGG-3′ hexanucleotide repeats of telomeric DNA by reverse transcription using its own RNA subunit as a template. Because telomerase is not expressed in most normal human cells, telomerase inhibition is considered an almost universal oncology target, and several clinical trials are under way (4). However, the future success of inhibiting telomerase to treat cancer is far from assured. Indeed, ∼10 to 15% of human cancers lack detectable telomerase activity (3), and many of these use an alternative lengthening of telomeres (ALT) mechanism (5). These ALT-expressing tumors would not be expected to respond to anti-telomerase therapies, and telomerase-expressing tumors could become resistant by switching to an ALT mechanism, as has recently been shown in mice (6). Here we present a brief history of ALT research, outline what is left to learn about the pathway, and propose it as a valuable drug target both alone and in combination with telomerase as a dual-targeted anticancer strategy.