UC San Francisco researchers have discovered how a mutation in the TERT promoter confers immortality on tumor cells. The research, published today in Cancer Cell found that patient-derived glioblastoma cells with TERT promoter mutations depend on a particular form of GABP for their survival. GABP is critical to the workings of most cells, but the researchers discovered that the specific component of this protein that activates mutated TERT promoters, a subunit called GABP-ß1L, appears to be dispensable in normal cells: Eliminating this subunit using CRISPR-based gene editing dramatically slowed the growth of the human cancer cells in lab dishes and when they were transplanted into mice, but removing GABP-ß1L from healthy cells had no discernable effect.
"These findings suggest that the ß1L subunit is a promising new drug target for aggressive glioblastoma and potentially the many other cancers with TERT promoter mutations," said study senior author Joseph Costello, Ph.D.
Immortality is one of the key traits of cancer cells. Tumor cells become immortal by activating telomerase, often through mutations in TERT, one of the two genes that encodes the telomerase complex, which enables them to grow and spread unfettered by the limitations of normal cells. Efforts to treat cancers with drugs that block telomerase have mostly proven too toxic to patients because they interfere with telomere maintenance in stem cells.
But recent research has suggested that more than 50 types of human cancers may be caused not by a defective TERT gene itself, but by mutations in the TERT promoter. These mutations enable GABP to bind to the TERT promoter and activate it, other studies had found, which was strange because in healthy cells GABP and TERT usually have nothing to do with one another.
"This was really intriguing to us," Costello said. "You can't create a drug to target a promoter itself, but if we could identify how GABP was binding to the mutated promoter in these cancers, we might have a remarkably powerful new drug target."
Costello's team studied human glioblastoma cell lines and primary tumor cells derived from advanced-stage glioblastoma patients and showed that the cells' mutations create two adjacent sequences of DNA in the TERT promoter that make a perfect landing pad for a particular form of the GABP transcription factor complex containing four subunits, one of which was GABP-ß1L.
The researchers showed that this GABP-ß1L-containing form of GABP is required to activate TERT and drive cancer growth, but that it appears not to be essential for healthy cells. When the researchers used multiple techniques, including CRISPR-based gene editing, to eliminate the GAPB1L subunit from glioblastoma cells in laboratory cultures, the cells' growth dramatically slowed. The researchers then implanted patient-derived glioblastoma cells into mice and showed that while unedited cells grew aggressively and quickly proved fatal for the animals, cells edited to lack GAPB1L grew much more slowly and were less lethal.
"In theory what we have now is a therapeutic target that is not TERT itself, but a key to the TERT switch that is not essential in normal cells," Costello said. "Now we have to design a therapeutic molecule that would do the same thing."