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Study reveals how promising cancer drug works for best use

A study describes for the first time how a promising anti-cancer drug – currently in clinical trials – works to effectively kill cancer cells.

The drug, called an ATR inhibitor, has been shown to successfully fight cancer by disabling a cell’s DNA protection system, but until now scientists have not fully understood the biological mechanisms that make it work.

The results, published July 13 in the journal Nucleic Acids Research, should inform doctors currently doing clinical trials on optimal ways to use ATR inhibitors, and how to combine them with other cancer-fighting therapies, in a range of different types of cancer.

“Our work provides an [understanding] for how these inhibitors work and helps come up with a logical rationale for how to use them in the clinic,” said Marcus Smolka, associate professor in the Department of Molecular Biology and Genetics, a member of the Weill Institute for Cell and Molecular Biology, and senior author of the paper. Graduate student Dongsung Kim and postdoctoral researcher Yi Liu, both in Smolka’s lab, are co-first authors of the paper.

When DNA breaks, a kinase (a catalyzing enzyme) called ATR senses the damage to DNA in cells. The researchers found that when needed, ATR signals the start of a process that leads to the expression of proteins called homologous recombination (HR) factors, which are key players in the DNA repair system. ATR inhibitors block ATR signaling and prevent the expression of HR proteins and DNA repair. It turns out, the genomes of cancer cells break apart and are damaged more often than normal cells, partly because they replicate rapidly in a deregulated manner.

“Cancer cells become addicted to ATR because they need more of that protection [than normal cells]. Otherwise their DNA just breaks down to pieces and the cancer cells are not viable anymore,” Smolka said.

In the study, the researchers used a system for measuring HR repair in cells and then acquired human cancer cell lines (in culture), exposed them to ATR inhibitors and monitored HR levels. “We were expecting that if we treat for one or two days there was going to be a huge drop in HR,” Smolka said, but they found only a mild decrease. After continuing to treat the cells over eight days, they found HR decreased almost tenfold. Without HR proteins to repair DNA, the cancer cells died. “If you really want to affect HR in cancer cells, you need to inhibit it chronically for a long time,” he said.

They discovered that the ATR inhibitors prevent the synthesis of new HR proteins, but it takes a few days for existing proteins already in the system to degrade, which explained the delay in the reduction of HR.

Certain cancers, such as breast and ovarian cancers with BRCA mutations, lack a HR-mediated repair system. An FDA-approved drug called a PARP inhibitor has been approved for these specific cancers, as they generate DNA damage in the cancer cells during replication. The researchers believe that ATR and PARP inhibitors could be combined as a very effective system against other cancers (aside from BRCA mutated cancers); ATR inhibitors could disable the HR DNA repair system in cancers that use HR, which would then allow PARP inhibitors to generate even more damage and effectively kill cancer cells. The strategy would also allow clinicians to use even lower doses of ATR inhibitors, further reducing potential side effects for patients.

Normal cells are not affected by ATR inhibitors when the therapy is administered in low doses because their DNA has less need for repair than cancer cells, which makes it an effective treatment, Smolka said.

In future steps, the researchers plan to test ATR inhibitors in live mice with tumors, explore their effectiveness in different cancer types, calibrate doses, experiment with drug combinations, and collaborate with clinicians conducting clinical trials.

Raimundo Freire, a researcher at the Institute de Tecnologias Biomedicas in Tenerife, Spain, is a co-author.

The study was funded by the National Institutes of Health and the Spanish Ministry of Economy and Competitiveness.

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Lindsey Hadlock