Cancer: New compound boosts chemo, prevents treatment resistance
Researchers may have found a way to stop cancer cells from defending themselves against chemotherapy. In a new mouse study, blocking a DNA repair pathway prevented cancer cells from surviving or becoming resistant to treatment.
Graham Walker, the American Cancer Society Research Professor of Biology at the Massachusetts Institute of Technology (MIT) in Cambridge, is one of the senior authors of the new paper.
In his previous research, Prof. Walker studied a DNA repair process that cancer cells rely on to avoid the damage of chemotherapy. This process is called translesion synthesis (TLS).
As the researchers explain, healthy cells can normally repair DNA by accurately 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, TLS uses specialized TLS DNA polymerases. Polymerases are enzymes that can make copies of DNA. Normal DNA polymerases copy DNA accurately, but TLS DNA polymerases replicate damaged DNA in a less accurate fashion.
Why chemo 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 TLS DNA polymerases are really error-prone, they are accountable for nearly all of the mutation that is induced by drugs like cisplatin,” explains co-senior study author Michael Hemann, an associate professor of biology at MIT.
Cisplatin is a chemotherapy drug that doctors prescribe to treat various forms of cancer, including “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 often resistant to cisplatin. The drug also has numerous side effects, such as “severe kidney problems, allergic reactions, decrease[d] immunity to infections, gastrointestinal disorders, hemorrhage, and hearing loss.”
This is why, in the new study, the scientists set out to enhance the power of this drug. “It’s very well established that with these frontline chemotherapies that we use, if they don’t cure you, they make you worse,” says Hemann.
“We’re trying to make the therapy work better, and we also want to make the tumor recurrently sensitive to therapy upon repeated doses,” he adds.
Pei Zhou, a professor of biochemistry at Duke University in Durham, NC, and Jiyong Hong, a professor of chemistry at Duke University, are also senior authors of the new study, which now appears in the journal Cell.