Small Molecule Jams Cancer’s Ability to Develop Resistance

The ability of tumor cells to become resistant to cancer treatment is a major cause for concern, underlying as much as 90% of deaths related to the disease. To combat this issue, scientists at Duke University School of Medicine are working on a small molecule drug that may stop cancer cells from becoming resistant to chemotherapy. A paper describing their progress was published this week in Cell.

A common strategy for many current cancer drugs is to damage DNA’s replication machinery, causing greater damage to rapidly dividing cancer cells than it does to healthy cells. However, cancer cells can sometimes find ways to proliferate even while damaged by switching out their replication machinery with a sloppier, but nevertheless effective, replacement that covers up the lesions and moves on. This process is known as translesion and is one of the major causes of cancer drug resistance. Scientists have identified the protein Rev1 as a key driver of translesion and have even disrupted it through genetic means, but have never been able to target it with small molecules.

In the current study, the researchers screened 10,000 small molecule compounds and found a molecule called JH-RE-06 that appeared to effective target Rev1.

Using x-ray crystallography, the scientists were able to visualize the interactions between Rev1 and JH-RE-06. It was observed that when Rev1 interacts with JH-RE-06, it dimerizes with another copy of itself and becomes locked in this configuration, thereby preventing it from helping cancer cells survive.

Tests in human cancer cell lines showed that JH-RE-06 treatment enhanced the ability of several forms of chemotherapy to kill cells, while suppressing their ability to mutate and gain resistance. In mouse models treated with JH-RE-06 and the anti-cancer drug cisplatin showed a reduction in tumor growth and longer survival.

While there is still much work to be done before the compound’s clinical viability is established, the Duke University team are excited for these preliminary proof-of-concept results. They are currently working to further improve the pharmacological properties of the drug.

Image: Structure of the complex containing Rev1 and JH-RE-06. The two copies of the Rev1 protein are shown in dark and light blue, while the small molecule JH-RE-06 wedged in between is shown in bright pink. Image courtesy of Pei Zhou of Duke University.