Study identifies potential new cancer drug targets

Telomeres on chromosomes

A new study has provided insights into the biological mechanism that supports survival of hard-to-treat cancers.

In the new study, led by scientists at The Institute of Cancer Research and published in Nature Communications, researchers identify a new cellular role of a protein called EXD2 nuclease and, importantly, its role in the so-called ALT (alternative lengthening of telomeres) pathway.

The study, which was funded by the ICR and Cancer Research UK, also provides potential new targets for cancer drugs.

Professor Wojciech Niedzwiedz, Leader of the Genome Instability and Cancer group at the Institute of Cancer Research, London, said: “Some 10-15% of cancers support cell proliferation via the ALT mechanism, including up to 50% of hard-to-treat osteosarcomas, soft tissue sarcomas and primary brain tumours – including childhood brain tumours. These ALT-reliant cancers are highly aggressive and there are very limited treatment options. Understanding how these tumours maintain telomeres to sustain unlimited growth, at the molecular level, is therefore essential to help develop new therapies.

“Our study expands on our understanding of how cancer cells look after their telomeres in order to achieve immortality. Importantly, it also uncovers new synthetic lethal interactions within the ALT pathway and as such, paves the way for the development of new anti-cancer therapies.’’

The ALT pathway

Telomeres act like a protective cap during normal cell division but shorten every time a cell divides, which makes cell death inevitable over time. This means that to survive and proliferate, cancer cells must subvert this natural process of telomere shortening, maintaining the length of their telomeres.

They achieve this through two different mechanisms: either through activation of telomerase – an enzyme that promotes lengthening of telomeres – or via the ALT process. There is very limited knowledge about how ALT works – and yet it’s one of the fundamental pathways in those cancers.

The researchers established that EXD2 is essential to promote telomere maintenance via a process called break-induced replication, and discovered that the loss of EXD2 in ALT cells resulted in telomere shortening.

Importantly, the study also found that EXD2 depletion killed ALT-dependent cancer cells if combined with the loss of other DNA repair proteins – such as BLM, DNA2 and POLD3.

The work provides a proof-of-concept that targeting EXD2 nuclease in addition to either one of those three gene products could be a new strategy to eradicate tumours relying on the ALT mechanism for survival.

Professor Niedzwiedz is aiming to further develop aspects of his programme focusing on targeting EXD2 nuclease in cancer in collaboration with industry.

Edited by Diana Spencer, Senior Digital Content Editor, Drug Discovery World

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