The unlimited proliferative capacity of cancer cells relies upon the activation of a telomere maintenance mechanism. Approximately 85-90% of all human cancers activate the ribonucleoprotein enzyme telomerase to lengthen telomeres, whilst the remaining 10-15% utilise recombination-directed replication via the Alternative Lengthening of Telomeres (ALT) mechanism. ALT is prevalent in aggressive tumours of mesenchymal origin, which typically have a poor prognosis. Successful therapeutic targeting of telomere maintenance in cancers will require the development of both telomerase and ALT inhibitors.

We have identified that the BTR dissolvase complex, which is comprised of the RecQ helicase BLM, topoisomerase IIIα (TOP3A) and the RMI proteins RMI1 and RMI2, is required for ALT-mediated telomere synthesis through a mechanism analogous to break-induced replication. The role of BLM in ALT is dependent on both its helicase activity, and its ability to form the BTR complex. Depletion of the complex significantly inhibits ALT, implicating BTR disruption as a promising avenue in the development of ALT specific inhibitors.

In this study, we treated cancer cells with the small molecule inhibitor ML216, which inhibits BLM helicase activity. ML216 resulted in decreased ALT activity and telomere shortening. To develop more targeted inhibitors, we have optimised overexpression and purification of the BTR components in human cells. We are using high throughput Alphascreen technology to screen chemical libraries, custom libraries, and custom-made peptides for their ability to disrupt protein: protein interactions within the BTR complex. Ultimately, the aim is to develop chemical modifiers that specifically inhibit ALT cancer cell growth.