A new compound has been discovered that disables a key DNA repair pathway involved In cancer drug resistance. The potential drug, found by researchers at MIT and Duke University, enhances the effects of cisplatin, a popular cancer chemotherapy. The paper appears in the June 6 issue of Cell.
Cisplatin is a DNA-damaging alkylating agent. It is a first treatment option for at least a dozen types of cancer, including testicular, ovarian, bladder, head and neck, esophageal, lung, breast, cervical, stomach, and prostate cancers, as well as advanced bladder cancer, metastatic ovarian or testicular cancer.
But while the drug is often effective in initially eradicating tumors, they frequently grow back. Studies suggest this is because as they develop, tumors become reliant on a DNA repair system that is not common to normal cells—one that involves specialized TLS DNA polymerases.
“Because these TLS DNA polymerases are really error-prone, they are accountable for nearly all of the mutation that is induced by drugs like cisplatin,” said Michael Hemann, an associate professor of biology, a member of MIT’s Koch Institute for Integrative Cancer Research, and a senior author of the study. These mutations can lead to drug resistance. “It’s very well-established that with these frontline chemotherapies that we use, if they don’t cure you, they make you worse,” Hemann added.
After showing that impeding translesion synthesis with RNAi could impair DNA repair in tumors, the researchers set out to find a small-molecule drug that could have the same effect.
One of the key TLS DNA polymerases required for translesion synthesis is Rev1. Its primary function is to recruit a second TLS DNA polymerase that comprises a complex of the Rev3 and Rev7 proteins. The researchers focused on these molecular interactions.
The Duke researchers performed a screen of about 10,000 potential drug compounds and identified one that binds tightly to Rev1, preventing it from interacting with Rev3/Rev7 complex. Next, that compound was tested in combination with cisplatin in several types of human cancer cell lines. The combination was found to be much more effective than cisplatin on its own. Also, cancer cells that survived were much less able to generate new mutations. The drug combination was then tested in mice with human melanoma tumors. The tumors treated with the combination shrank much more than those treated with cisplatin alone.
“We’re trying to make the therapy work better, and we also want to make the tumor recurrently sensitive to therapy upon repeated doses,” says Hemann,
The Duke Lab is now working on developing variants of the compound that are best suited for testing in human patients. Meanwhile, Hemann and other collaborators are further investigating how the drug compound works, which they believe could help to determine the best way to use it.
“That’s a future major objective, to identify in which context this combination therapy is going to work particularly well,” Hemann says. “We would hope that our understanding of how these are working and when they’re working will coincide with the clinical development of these compounds, so by the time they’re used, we’ll understand which patients they should be given to.”
Pei Zhou, a professor of biochemistry at Duke University and Jiyong Hong, a professor of chemistry at Duke, are also a senior authors of the paper. Its lead authors are former Duke graduate student Jessica Wojtaszek, MIT postdoc Nimrat Chatterjee, and Duke research assistant Javaria Najeeb.