Tousled-like kinases (TLKs) are a potential therapeutic target for cancer treatment due to their central role in DNA repair and replication. The latest work concludes that TLK inhibition activates the innate immune system, a very important factor in the response to cancer.

"We believe the TLKs are promising targets for cancer therapy and want to understand more about how they work and how cells respond to their reduction or loss," says the senior author.

The group of researchers had previously observed that reduced TLK activity made cancer cells more sensitive to some therapeutic agents. Now, they have found that blocking TLKs triggers an alternative telomere lengthening system (ALT), a pathway used by many cancers, including some of the most aggressive ones like glioblastoma, to maintain telomeres and allow cells to continue dividing.

The group of researchers has discovered that activation of the ALT pathway triggers the innate immune system, potentially attracting immune cells, such as macrophages and T lymphocytes. "The activation of innate immunity in cancer has recently become an active area of research as it has become clear that the innate immune response influences chemotherapy and immunotherapy," comments the author.

In DNA, not all regions have the same function. Some regions contain genes with the information necessary to make proteins, but there are other regions, called heterochromatin, that have a regulatory and structural function, but do not contain genes that give rise to proteins. Another effect of TLK inhibition, observed in this study, is that this heterochromatin, which is usually compacted, ceases to be so, thereby becoming more accessible to the RNA production machinery and leading to an altered composition in the cell.

"This could help us understand our previous observation that TLK depletion caused replication stress and help us exploit the effects of TLK depletion for cancer therapy," says the first author of the study.

https://www.irbbarcelona.org/en/news/tlk-protein-inhibition-activates-the-innate-immune-system

https://www.cell.com/cell-reports/fulltext/S2211-1247(20)30968-2

http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Ftousled-like-kinases&filter=22