9 June 2017
Prostate cancer is a major global cause of death for men worldwide. It is also a cancer type marked by a specific tumour-suppressor deficiency: up to 70% of prostate cancers show loss of the gene encoding PTEN, a tumour suppressor protein required for inhibiting cell division and promoting cell death.
Alan Wang and Ronald DePinho at the University of Texas MD Anderson Cancer Center and co-workers studied the pattern of gene deletions in prostate cancer using various genome databases. They uncovered a new therapeutic target by screening for synthetic essential genes: genes that are deleted in some prostate cancers, but are consistently retained in those lacking PTEN.
The notion of finding therapeutic targets by studying gene deletions is not new. Previous studies have demonstrated the effectiveness of this approach in breast cancer types marked by BRCA1 deficiency. By screening for mutated genes that are harmless in most breast cancers but deadly in those lacking BRCA1, researchers identified the gene encoding PARP1 enzymes as a therapeutic target in BRCA1-deficient cancers. The finding ultimately led to the development of new treatment regimens for breast and ovarian cancers based on PARP1 inhibitors.
In the new approach, Wang and his team searched for deleted and retained genes. After several screens of the Cancer Genome Atlas database and other prostate cancer databases, they identified synthetic essential genes that could serve as therapeutic targets in PTEN-deficient cancers. Among them were genes encoding PARP1 and PLK enzymes, whose inhibitors are already in use for the treatment of prostate, colorectal and endometrial cancers.
The researchers also identified the gene encoding the chromatin remodelling factor CHD1 as an additional potential therapeutic target. To validate this, they genetically edited PTEN-deficient prostate and breast cancer cell lines so that their CHD1 expression was reduced. They found that CHD1 depletion profoundly and specifically suppressed cell proliferation, cell survival and tumorigenic potential of the cancer cells. This suggests that CHD1 inhibitors might be effective against PTEN-deficient prostate cancer.
The study demonstrates the feasibility of finding therapeutic targets in cancers marked with specific tumour-suppressor deficiencies using the synthetic essentiality approach. “Our approach to identify targets for deleted tumour suppressors will pave [additional] ways for cancer therapeutic development,” says Wang.
Zhao, D., Lu, X., Wang, G., Lan, Z., Liao, W. et al. Synthetic essentiality of chromatin remodelling factor CHD1 in PTEN-deficient cancer. Nature (2017).| article