Genetic changes in cancer cells reveal potential drug target

Targeting the PELO gene eliminates tumour cells from cancers caused by mutations or deletions of two specific genes.

Traditional targeted cancer therapies inhibit specific proteins encoded by cancer-causing genes. An alternative strategy leverages synthetic lethality. This is where the mutation/deletion of one gene alone is not 'lethal', but its combined loss with another gene leads to cancer cell death. This multi-institutional study identified PELO as a promising target in cancers caused by FOCAD deletions or TTC37 mutations/deletions. These genetic alterations are linked to various cancers, making PELO inhibition a potential therapeutic approach.

'These cancers are a huge unmet medical need, because we don't have effective drugs for them,' said Dr Francisca Vazquez, co-senior author of this study at the Broad Institute, Massachusetts. She continued, 'Targeting synthetic lethalities is a good way to expand the repertoire of tumours we're able to treat.'

This Nature study explored why five percent of adult cancers depend on the PELO gene for survival. To achieve this, the researchers used the Cancer Dependency Map (DepMap) to analyse genetic vulnerabilities in over 1200 cancer cell lines (see BioNews 1222). They found that cells with FOCAD deletions or TTC37 mutations were highly dependent on PELO. Cell-based experiments confirmed that removing PELO from these mutated cells led to cell death. This revealed new, independent synthetic lethal relationships between PELO and TTC37, as well as PELO and FOCAD.

Speaking about the DepMap resource, Dr Vazquez said, 'This new synthetic lethality we found shows how powerful the DepMap datasets can be.' Dr Vazquez is also the director of DepMap at the Broad Institute.

This research also uncovered a common cancer mechanism linking these two synthetic lethal gene pairs: damage to the superkiller complex (SKIc). The SKIc removes RNA from stalled ribosomes. When FOCAD deletions or TTC37 mutations disrupt the SKIc, cancer cells become dependent on PELO to restart stalled ribosomes. Blocking PELO in these mutated cells triggers a severe cellular stress response, leading to cancer cell death.

A separate Nature study reinforced these findings, confirming that FOCAD deletions and TTC37 mutations disrupt the SKIc, increasing PELO dependence. Additionally, this study also identified another gene in this synthetic lethal relationship: HBS1L. PELO and HBS1L work together to restart stalled ribosomes, suggesting that both genes could serve as drug targets for these specific forms of cancer.

In the future, the Broad Institute group aims to further investigate the roles of PELO and the SKIc in human cells. They would also like to determine the level of PELO inhibition required for an effective therapeutic response. The authors conclude, 'Our findings underscore the potential of DepMap to uncover novel therapeutic targets and functional interactions, opening new avenues for therapeutic interventions and fundamental biological understanding.'