Loss of Gene Copies Makes Cancer Cells Vulnerable to Drug Treatment

Cancer cells often lose "back-up" copies of critical genes, a state that renders them vulnerable to drug treatments that would not affect normal cells that have multiple copies of these genes.

Due to genome instability, most cancers exhibit loss of regions containing tumor suppressor genes. Loss of these tumor suppressor genes is often accompanied by loss of other nearby genes.

Investigators at the Dana-Farber Cancer Institute (Boston, MA, USA) performed integrated analyses of genome-wide copy number and RNAi profiles on more than 3,100 samples obtained from various well-documented collections of cancer cells. From an initial pool of 5,312 genes, the investigators identified 56 that were critical for cancer cell survival but only existed in a single copy in the cancer cells. These critical genes were dubbed CYCLOPS genes (for Copy number alterations Yielding Cancer Liabilities Owing to Partial losS).

Of the 56 CYCLOPS genes the most critical was deemed to be PSMC2 (proteasome 26S subunit, ATPase, 2), which encodes an essential member of the 19S proteasome.

In experiments described in the August 16, 2012, online edition of the journal Cell the investigators administered a PSMC2-blocking agent to mice whose tumors lacked a copy of the PSMC2 gene. Blocking PSMC2 killed the cancer cells, and the tumors regressed dramatically.

"This study represents a bringing-together of two approaches to understanding the basic mechanics of cancer," said senior author Dr. William Hahn, associate professor of medicine at the Dana-Farber Cancer Institute. "One involves research into the effect of gene copy number changes on cancer. The other is a systematic exploration of the function of individual genes. By combining these approaches, we have been able to identify a distinct class of cancer-cell vulnerabilities associated with the copy number loss of essential genes. We found that they are heavily involved in the components of three critical cell structures: the spliceosome, the ribosome - which use genetic information to construct proteins for the cell- and the proteasome, which is a vital protein machine that disposes of unneeded protein material. This suggests that they are required for cell proliferation or survival."

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Dana-Farber Cancer Institute