Graham C. Walker, Ph.D.
Massachusetts Institute of Technology
NIEHS grantees have discovered that a small molecule compound can block a DNA pathway that helps tumors withstand damage from chemotherapy drugs. The compound targets translesion synthesis, a damage tolerance process that allows specialized enzymes that copy DNA to replicate past damaged DNA. Some tumors can withstand damage from chemotherapy drugs by relying on translesion synthesis, which allows them to survive, but it can also introduce new mutations that allow cancer cells to become resistant to future treatment.
Researchers screened 10,000 small molecule compounds looking for a molecule to block or inhibit Rev1, a key protein involved in translesion synthesis. They found that a molecule called JH-RE-06 appeared to block Rev1 from interacting with other key proteins in the translesion synthesis pathway. The researchers used X-ray crystallography to visualize the interactions between Rev1 and JH-RE-06 and found that JH-RE-06 pairs up with Rev1 and locks it into a chemical structure where it can no longer help cancer cells survive.
The researchers then tested the molecule in human cancer cell lines. They showed that it enhanced the ability of several different types of chemotherapy to kill cells, while also suppressing their ability to mutate in the presence of DNA-damaging drugs. In a mouse model of human melanoma, they found that not only did the tumors stop growing in mice treated with a combination of the chemotherapy drug cisplatin and JH-RE-06, those mice also survived longer.
Citation: Wojtaszek JL, Chatterjee N, Najeeb J, Ramos A, Lee M, Bian K, Xue JY, Fenton BA, Park H, Li D, Hemann MT, Hong J, Walker GC, Zhou P. 2019. A small molecule targeting mutagenic translesion synthesis improves chemotherapy. Cell 178(1):152-159.e11.