Nav: Home

A molecular glue to overcome cancer drug resistance?

June 07, 2019

DURHAM, N.C. -- Scientists have discovered a small molecule drug that may stop cancer cells from becoming resistant to chemotherapy. Drug resistance is a major cause of cancer relapse and is responsible for as much as 90% of deaths related to the disease.

The new compound, which was tested in an animal model of melanoma, could make current chemotherapies more powerful. It works by thwarting cancer's ability to survive, evolve, and adapt to the DNA damage created by traditional chemotherapy drugs like cisplatin.

"Chemotherapies are often effective the first time around, but then the cancers mutate and become resistant to that drug, and the next, and the next," said senior study co-author Pei Zhou, Ph.D., a professor of biochemistry at Duke University School of Medicine.

"It reminds me of Boggarts, those shapeshifting creatures from Harry Potter that morph from one scary thing to another. The beauty of this approach is that you essentially freeze the Boggart in its current form, so you can kill it off for good."

The study was published June 6 in Cell.

In their simplest form, cancer cells are normal cells that are growing out of control. Each time these cells divide, the DNA within them must replicate to generate new copies to go inside each new cell. The first chemotherapy drugs were based on the rationale that rapidly growing cancer cells would be more sensitive to damage to their DNA. Drugs like cisplatin are designed to damage DNA, causing the sensitive replication machinery normally tasked with copying each strand to stall. If DNA replication is stalled for too long, cell division halts, and cells die.

The strategy is brutal and effective, even curative in some cases. But long-term, it often fails, as cancer cells figure out a way to proliferate even in the presence of DNA damage.

"The cancer cells often swap out the high fidelity replication machinery, which usually does the copying, with a sloppy replacement that covers up the lesions and moves on," said Zhou. "As a result, the cells survive, but with mutations in their DNA."

Because this process, known as translesion synthesis, is a major cause of cancer drug resistance, it has become a major area of study in cancer research. Scientists have identified a key protein involved, named Rev1, and have even disrupted it through genetic means -- works done in the laboratories of Graham C. Walker and Michael T. Hemann at MIT, both senior co-authors of this study. However, attempts to do the same with small molecules had never succeeded, presumably because the protein lacked an obvious binding pocket that a potential drug could exploit.

In this study, Zhou and his collaborators at Duke, MIT, and the University of Rhode Island decided to try their luck at finding a small molecule to block or inhibit Rev1. They screened 10,000 small molecule compounds, and were surprised to find that one -- a molecule called JH-RE-06 -- appeared to do the trick.

The researchers used a technique called x-ray crystallography to visualize the unexpected interactions between Rev1 and JH-RE-06. They found that when Rev1 interacts with JH-RE-06, it pairs up or dimerizes with another copy of itself, creating a binding pocket where there wasn't one before. When Rev1 is locked up in this dimer, it can no longer help cancer cells survive and attain their shape-shifting powers.

The researchers then tested the new molecule in human cancer cell lines and showed that it enhanced the ability of several forms of chemotherapy to kill cells, while also suppressing their ability to mutate in the presence of DNA-damaging drugs. Finally, they tested it in a mouse model of human melanoma. They found that not only did the tumors stop growing in mice treated with a combination of cisplatin and JH-RE-06, but also that those mice survived longer.

Senior study co-author Jiyong Hong, PhD, a professor of chemistry at Duke, said that they are currently creating versions of JH-RE-06 that have enhanced pharmacologic properties that could make it an even more attractive drug. "This is a great proof of principle that it is possible to target this protein, but we have a lot of work to do to turn this lead compound into a viable candidate that we can take to the clinic."
-end-
The lead authors of the paper are former Duke graduate student Jessica Wojtaszek, MIT postdoc Nimrat Chatterjee, and Duke graduate student Javaria Najeeb.

The research was supported in part by grants from the National Cancer Institute (CA191448 and CA213042), the National Institutes of Environmental Health Sciences (ES028303 and ES028865), the Alexander and Margaret Stewart Trust, Duke University, and Center for the Precision Medicine at MIT.

CITATION: "A Small Molecule Targeting Mutagenic Translesion Synthesis Improves Chemotherapy," Jessica L. Wojtaszek, Nimrat Chatterjee, Javaria Najeeb, Azucena Ramos, Minhee Lee, Ke Bian, Jenny Y. Xue, Benjamin A. Fenton, Hyeri Park, Deyu Li, Michael T. Hemann, Jiyong Hong, Graham C. Walker, and Pei Zhou. Cell, June 6, 2019. DOI: 10.1016/j.cell.2019.05.028.

Duke University

Related Chemotherapy Articles:

Chemotherapy drug may increase vulnerability to depression
A chemotherapy drug used to treat brain cancer may increase vulnerability to depression by stopping new brain cells from growing, according to a new King's College London study out today in Translational Psychiatry.
Sperm changes documented years after chemotherapy
A Washington State University researcher has documented epigenetic changes in the sperm of men who underwent chemotherapy in their teens.
Depressed patients are less responsive to chemotherapy
A brain-boosting protein plays an important role in how well people respond to chemotherapy, researchers report at the ESMO Asia 2016 Congress in Singapore.
Breast cancer study predicts better response to chemotherapy
It is known from previous research that the ER-beta estrogen receptor often has a protective effect.
Personalizing chemotherapy to treat pediatric leukemia
A team of UCLA bioengineers has demonstrated that its technology may go a long way toward overcoming the challenges of treatment for acute lymphoblastic leukemia, among the most common types of cancer in children, and has the potential to help doctors personalize drug doses.
More Chemotherapy News and Chemotherapy Current Events

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Anthropomorphic
Do animals grieve? Do they have language or consciousness? For a long time, scientists resisted the urge to look for human qualities in animals. This hour, TED speakers explore how that is changing. Guests include biological anthropologist Barbara King, dolphin researcher Denise Herzing, primatologist Frans de Waal, and ecologist Carl Safina.
Now Playing: Science for the People

#534 Bacteria are Coming for Your OJ
What makes breakfast, breakfast? Well, according to every movie and TV show we've ever seen, a big glass of orange juice is basically required. But our morning grapefruit might be in danger. Why? Citrus greening, a bacteria carried by a bug, has infected 90% of the citrus groves in Florida. It's coming for your OJ. We'll talk with University of Maryland plant virologist Anne Simon about ways to stop the citrus killer, and with science writer and journalist Maryn McKenna about why throwing antibiotics at the problem is probably not the solution. Related links: A Review of the Citrus Greening...