Scientists have identified 56 genes that are essential to cancer cell survival and may represent accessible targets for therapeutic development. In each case only one copy of the target gene is present in the cancer cell due to copy number loss resulting from genomic instability. For each identified gene, inhibiting the remaining copy in a cancer leads to cell death or blocks proliferation. And unlike classical oncogenes that drive cancer proliferation, most of the newly identified targets play roles in fundamental cellular processes and structures, including the spliceosome, ribosome, and proteasome.
The new discoveries are described by a team headed by researchers at the Broad Institute of Harvard and MIT, and the Dana Farber Cancer Institute. Rameen Beroukhim, M.D., William C. Hahn, M.D., and colleagues wanted to see which genes other than tumor suppressor genes affected by copy number loss were most critical to cell survival. “When tumor suppressor genes are lost, its common for several nearby genes, which play no role in cancer development, to be lost as well,” Dr. Hahn explains. Building on a theory proposed some 20 years ago that blocking the remaining copies of some of these neighbouring genes could be lethal to cancer cells, the team first analyzed the copy number profiles of over 3,100 samples from widely diverse samples, and found that most exhibited copy number loss affecting at least 11%, and up to 40% of their genomes. Many of the genes affected were recurrently lost due to passenger events or because of their proximity to a frequently deleted tumor suppressor gene.
The team then combined their data with data from project Achilles, a Dana-Farber initiative that has identified hundreds of genes critical to cancer cell proliferation. From a starting set of over 5,000 genes, they identified 56 for which loss of one copy in a cancer cell rendered the remaining copy essential to cancer cell survival.
Top of this list of 56 designated CYCLOPS (copy number alterations yielding cancer liabilities owing to partial loss) genes in terms of cancer cell dependence was the proteasome gene PSMC2. One copy of this gene was frequently lost in the cancer cells evaluated, but it was never missing altogether, indicating that at least one copy was essential for cell survival. To verify the importance of PSMC2 in vivo, the team blocked the remaining copy of the gene in mice carrying tumors that already lacked one copy of PSMC2. The result was dramatic tumor shrinkage. “It was a powerful demonstration of the potential of CYCLOPS genes to serve as targets for cancer therapy,” Dr. Beroukhim states.
The researchers say CYCLOPS genes represent a specific form of synthetic lethality, a phenomenon through which the combination of mutations in two or more genes leads to cell death, whereas a mutation in either one alone does not. But in the case of the CYCLOPS genes, blocking the target is lethal to cells completely independently to the pathways that actually drive the cancer itself. Drs. Beroukhim, Hahn et al., report their results in Cell, in a paper titled “Cancer Vulnerabilities Unveiled by Genomic Loss.”