More Evidence Suggests Passenger Gene Deletions Increase the Vulnerability of Cancer Cells to Chemotherapy

A second gene ENO2 also encodes enolase but with only 10%-25% of the activity of ENO1.

The investigators used short-hairpin-RNA (shRNA) to inhibit ENO2 activity in glioblastoma cells with or without active ENO1. Knocking down ENO2 in this fashion had no effect in glioblastoma cells with intact ENO1 but inhibited growth of glioblastoma cells with ENO1 deleted and caused complete loss of tumor-forming potential when injected into the brains of mice.

In another set of experiments glioblastoma cells with intact or deficient ENO1 but lacking ENO 2 activity were injected into the brains of mice. The animals were then treated with the enolase inhibitor phosphonoacetohydroxamate (PHAH). Results published in in the August 16, 2012, online edition of the journal Nature revealed that the treatment was highly toxic to ENO1-deleted cancer cells while having minimal effect on ENO1-intact cancer cells or normal human brain cells.

"The principle of collateral vulnerability caused by passenger deletions of redundant essential genes provides the basis for a new approach to identify potential targets and develop targeted therapies," said senior author Dr. Ronald DePinho, president of the MD Anderson Cancer Center. "These deletions are found in hundreds of genes in many types of cancer, so our model for glioblastoma multiforme should apply to developing personalized treatments for other cancers as well."

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