In a new mouse study, blocking a DNA repair pathway prevented cancer cells from surviving or becoming resistant to treatment.
Researcher Graham Walker of the American Cancer Society at the Massachusetts Institute of Technology (MIT) in Cambridge, one of the lead authors of the new paper in the journal Cell, had previously studied a DNA repair process in which cancer cells depend to prevent damage from chemotherapy. This process is called translesion synthesis (TLS).
As experts explain, healthy cells can normally repair DNA by precisely removing DNA damage. However, when cells become cancerous, they can no longer rely on this normal repair system. Instead, they use TLS, which is less accurate.
Specifically, translesion synthesis uses specialized TLS DNA polymerases. Polymerases are enzymes that can make copies of DNA. Normal DNA polymerases copy DNA precisely, but TLS DNA polymerases replicate damaged DNA less precisely.
Why do chemotherapy drugs need a boost?
This “imperfect” DNA replication process essentially leads to mutations that make cancer cells resistant to future DNA-damaging treatments.
“Because these polymerases are really error prone, they are responsible for almost all mutations induced by drugs like cisplatin,” explains study co-author Michael Hemann, associate professor of biology at MIT.
Cisplatin is a chemotherapy drug that doctors prescribe to treat various forms of cancer, such as bladder, head and neck, lung, ovarian, and testicular cancers. It works by interfering with DNA repair, causing DNA damage and eventually inducing cancer cell death.
However, cancer cells are quite often resistant to cisplatin. The drug also has numerous side effects, such as “severe kidney problems, allergic reactions, decreased immunity to infections, gastrointestinal disorders, bleeding, and hearing loss.”
This is why, in the new study, the scientists set out to enhance the power of this drug. “With these first-line chemotherapies that we use, if they don’t cure you, they make you worse,” Hemann says. “We are trying to make the therapy work better, and we also want the tumor to be sensitive to repeated dose therapy,” adds the expert.
1 drug in 10,000 boosts cisplatin
In previous research, experts showed that for cisplatin to work,translesion synthesis had to be interrupted.Specifically, they found that reducing the expression of TLS polymerase Rev1 through RNA interference made the drug cisplatin much more effective at fighting lymphoma and lung cancer in mouse models, preventing recurrent tumors from becoming resistant to treatment.
In the new study, they looked at approximately 10,000 drug compounds with the potential to disrupt the TLS process.
Finally, found a drug that prevented it from interacting with other polymerases and proteins that are necessary for TLS to occur.The researchers tested this compound in combination with cisplatin on various types of human cancer cells and found that the combination killed many more cancer cells than the chemotherapy drug alone.
Also, cancer cells that survivedthey were less likely to form new mutations that would make them resistant to treatment.
“Because this new TLS inhibitor targets the mutagenic ability of cancer cells to resist therapy, it can potentially address the problem of cancer relapse, where cancers continue to evolve from new mutations and together pose a great challenge in treating cancer, “explains study co-author Nimrat Chatterjee.
The new compound
The scientists then tested the drug combination in a mouse model of melanoma with human cancer cells and saw that the tumors shrink much more when the scientists treated them with the drug combination than with cisplatin alone.
“This compound increased cell destruction with cisplatin and prevented mutagenesis, which we hoped would block this pathway,” clarifies Graham Walker.
In the future, the researchers plan to examine the mechanisms behind the effects of this combination. His goal is to start testing it in humans.
Referencia: 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, Pei Zhou. A Small Molecule Targeting Mutagenic Translesion Synthesis Improves Chemotherapy. Cell, 2019; DOI: 10.1016/j.cell.2019.05.028
