Researchers Say Molecule May Help Overcome Cancer Drug Resistance

A group of researchers from the University of Delaware has discovered that a deubiquitinase (DUB) complex, USP1-UAF1, may present a key target in helping fight resistance to platinum-based anticancer drugs. The research team’s findings were published online in Nature Chemical Biology.

Zhihao Zhuang, associate professor in the Department of Chemistry and Biochemistry at UD, and his team studied a DNA damage tolerance mechanism called translesion synthesis (TLS). Enzymes known as TLS polymerases synthesize DNA over damaged nucleotide bases, followed by replication after lesion. The enzymes have been linked with building cancer cell resistance to certain cancer drugs including cisplatin. Cisplatin is used in treatment of ovarian, bladder, and testicular cancers which have spread.

“Cancer drugs like cisplatin work by damaging DNA and thereby preventing cancer cells from replicating the genomic DNA and dividing. However, cancer cells quickly develop resistance to cisplatin, and we and other researchers suspect that a polymerase known as Pol η is involved in overcoming cisplatin-induced lesions,” Professor Zhuang said.

The team found that USP1-UAF1 may play a crucial role in regulating DNA damage response. A new molecule ML323 can be used to inhibit processes such as translesion synthesis. Zhuang said, “Using ML323, we studied the cellular response to DNA damage and revealed new insights into the role of deubiquitination in both the TLS pathway and another one called the Fanconi anemia, or FA, pathway. We’re very encouraged by the fact that a single molecule is effective at inhibiting the USP1-UAF1 DUB complex and disrupting two essential DNA damage tolerance pathways.”

Exposing lung cancer cells to cisplatin alone and to a combination of cisplatin and ML323 showed that the reduction in EC50 was greater when the combination was used. EC50 is a common measure of efficacy of small-molecule drugs. Zhuang said the results showed that the inhibitor effectively restores cisplatin’s ability to fight cancer cells.

“Cancer treatment is increasingly moving to combination therapies to make it more effective and less toxic to normal cells. I think our findings from this work indicate that the USP1-UAF1 DUB inhibitor not only shows promise in fighting cancer but also can help us in investigating the complex biology of DNA damage responses,” Zhuang said.