New prospects for targeting telomerase beyond the telomere

Key Points Telomerase is a ribonucleoprotein complex responsible for maintaining chromosome-end structures called telomeres. Telomerase activity enables unlimited cell proliferation (immortality) in diverse human cancers. Despite the cloning of the catalytic component of telomerase approximately 20 years ago and the central role of telomerase in diverse cancers, only one small-molecule telomerase inhibitor, imetelstat, has been tested in clinical trials. Components of the telomerase complex have extra-telomeric activities that may contribute to cancer cell survival, proliferation and malignancy. Recent advances in drug discovery technology may be leveraged in the identification and development of novel small-molecule inhibitors that simultaneously disrupt telomere maintenance and the non-canonical activities of telomerase components. This Review outlines strategies for harnessing state-of-the-art drug discovery techniques to find novel cancer therapeutics that exploit multifaceted biological functions of core components of telomerase. Given the important roles of telomerase in cancer, it is an attractive therapeutic target. This Review discusses our current knowledge of telomerase activities in cancer and strategies for therapeutic exploitation. Telomerase activity is responsible for the maintenance of chromosome end structures (telomeres) and cancer cell immortality in most human malignancies, making telomerase an attractive therapeutic target. The rationale for targeting components of the telomerase holoenzyme has been strengthened by accumulating evidence indicating that these molecules have extra-telomeric functions in tumour cell survival and proliferation. This Review discusses current knowledge of the biogenesis, structure and multiple functions of telomerase-associated molecules intertwined with recent advances in drug discovery approaches. We also describe the fertile ground available for the pursuit of next-generation small-molecule inhibitors of telomerase.