Study published online in PNAS, describes a novel druggable oncogenic driver gene in human gastrointestinal stromal tumours (GISTs).
The research team led by Professor Wang Yuexiang of the Shanghai Institute of Nutrition and Health (SINH) of the Chinese Academy of Sciences, together with Professor Jonathan Fletcher from Brigham Women’s Hospital and Harvard Medical School used whole exome sequencing and reported recurrent genomic inactivated DEPDC5 gene mutations in GIST. DEPDC5 was shown to be a chromosome 22q-targeting tumour suppressor, silenced by mutations in GIST specifically.
Chromosome 22q deletions are frequent chromosomal abnormalities in human GISTs, occurring in approximately 50 percent of GISTs, and are thought to contribute to the pathogenesis of this disease. This research uncovers the crucial gene in chromosome 22q that is related to the genomic alterations.
The evidence showed that inactivation of DEPDC5 promotes rapid increase in GIST cells by activating the mTORC1 signalling pathway and subsequently preventing cell cycle arrest. They demonstrated that DEPDC5 modulates the sensitivity of GIST to KIT inhibitors, and combination therapy using the mTOR inhibitor and KIT inhibitor may work better in GIST patients with DEPDC5 inhibition.
Recurrent genomic alterations and functional data validate DEPDC5 as a tumour suppressor contributing to GIST progression and biologically relevant target of frequent chromosome 22q deletions. The DEPDC5-inactivated mutation will be able to serve as a predictive course of GIST as they are associated with aggressive GISTs, where they promote GIST progression and reduce sensitivity to KIT indicators.
The inactivation of DEPDC5 gene has also been found to be associated with the disease mechanism of focal epilepsy. Thus, highlighting that recent therapeutic developments for focal epilepsy could also serve as anti-cancer drugs.