New Strategy May Thwart Glioblastoma Resistance

Temozolomide has been a first-line glioblastoma treatment for almost 20 years, but tumors can develop resistance to it. Researchers have developed a new approach that may overcome resistance by targeting cells lacking a key DNA repair enzyme (Science 2022;377:502–11).

Temozolomide attacks DNA by adding a methyl group to the oxygen atom in the base guanine. Healthy cells and about half of glioblastomas don't respond to the drug because they make ample amounts of the enzyme MGMT, which reverses this DNA alteration. But for unknown reasons, about half of glioblastomas have reduced MGMT production, leaving them vulnerable to temozolomide. In these tumors, cells try to use another DNA-mending mechanism, the mismatch repair (MMR) pathway, to restore their DNA. However, MMR cannot remove the altered guanine, leading to DNA breaks that cause the cells to die. Glioblastomas are continually accumulating mutations, and some tumors that lack MGMT become resistant to temozolomide when they pick up mutations that inactivate MMR.

A team led by Seth Herzon, PhD, and Ranjit Bindra, MD, PhD, of Yale University in New Haven, CT, devised an approach for killing MGMT-lacking tumor cells that doesn't depend on whether MMR is functional. Their idea was to create a drug that induces a DNA lesion that becomes more severe when it isn't fixed. Healthy cells with plenty of MGMT would repair the lesion quickly, the researchers predicted. But they also hypothesized that in cells without MGMT, as in about half of glioblastoma cells, the lesion would lead to cross-links between DNA strands, blocking replication and promoting apoptosis. Even if tumor cells accrue mutations that disable MMR, they could not survive.

To test the approach, the scientists synthesized a molecule dubbed KL-50 that produces a DNA lesion by affixing a fluoroethyl group to the oxygen in guanine. They studied a panel of isogenic cell lines that expressed or lacked MGMT and had functional or nonfunctional MMR. Comparing temozolomide with KL-50 in these cells, the researchers found that neither drug performed well when cells had MGMT and functional MMR. But when MGMT was absent and MMR was inactive, KL-50 was much better at killing cells than temozolomide.

The team also implanted tumors that lacked MGMT and working MMR into the brains of mice and gave the animals KL-50, temozolomide, or a control compound. Mice treated with KL-50 lived significantly longer than control animals and those that received temozolomide.

KL-50 “might offer hope for patients with MGMT-negative, mismatch repair–silenced tumors,” says Herzon. He and his colleagues have formed a company to further develop the drug, and they hope to begin clinical trials in 2024, he says.

Outside experts give the researchers credit for investigating a novel strategy. “Thinking about ways to overcome DNA damage repair is worthwhile,” says John de Groot, MD, of the University of California, San Francisco.

“Their approach is interesting,” adds Fabio Iwamoto, MD, of the Columbia University Vagelos College of Physicians and Surgeons in New York, NY.

However, both scientists raise questions about the study's methods and are skeptical that the approach will provide much clinical benefit. One significant limitation, Iwamoto says, is the lack of an in vivo comparison with lomustine, a treatment widely used against glioblastomas that has clinical activity against MMR-deficient tumors. And de Groot notes that temozolomide resistance could arise from many factors, including the cancer microenvironment, that may not respond to the new strategy. –Mitch Leslie

For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.