What if a new combination of cancer drugs could sound an alarm, alerting the body’s immune system to invoke a targeted response to cancer cells?

“Our study revealed that a combination of cancer drugs can do more than damage cancer-cell DNA to kill the cancer cells,” explains postdoctoral fellow Elodie Bournique, PhD.

“They can also trigger an ‘alarm signal’ inside the cancer cells that alerts the body to their presence and recruits immune cells to help eliminate them.”

Working with researchers in the laboratory of Rémi Buisson, PhD, an associate professor of biological chemistry at UC Irvine, Bournique found that when PARP inhibitors are combined with drugs that block the Topoisomerase 1 enzyme (TOP1) — a protein needed to manage DNA structure — they trap PARP1 on the damaged DNA.

“This causes additional DNA damage and activates an inflammatory pathway driven by NF-κB,” says Bournique, referring to the nuclear factor kappa-light-chain-enhancer of activated B cells.

NF-κB is a critical element in regulating the immune response.

“In simple terms,” says Bournique, “this drug combination may make cancer cells not only more damaged but also more visible to the immune system.”

DNA-Damaging Treatment

This work addresses a major challenge in cancer therapy: how to make DNA-damaging cancer treatments more effective.

“TOP1 inhibitors and PARP inhibitors are both used in cancer treatment, but we still do not fully understand how combining them changes cancer-cell behaviour,” says Buisson.

TOP1 inhibitors damage cancer cell DNA, while PARP inhibitors prevent the cells from repairing themselves.

“Our study reveals an additional and unexpected effect: when PARP1 is trapped on DNA lesions caused by TOP1 inhibition, it activates an ATM–NF-κB inflammatory signalling pathway,” says Buisson.

“This suggests that PARP inhibitors may not only increase cancer-cell killing but also help stimulate tumour-associated inflammatory signals that could influence immune responses.”

Their findings from the experimental study appear in a paper published in Nucleic Acids Research.

Next Steps

“Our next step is to determine whether this mechanism also occurs in tumour models that better reflect human cancer, including additional cancer cell lines, organoid systems and eventually in vivo models,” says Ambrocio Sanchez, a graduate student researcher who helped with the study.

“We also want to test whether the inflammatory signals induced by TOP1 and PARP inhibitor combinations can promote immune-cell recruitment or improve anti-tumour immune responses.”

A key goal will be to identify which tumour types are most likely to benefit from this therapeutic combination.

The researchers stress that the benefit of PARP inhibitors may depend on matching them with the right type of cancer therapy and the right tumour context.

“In the future,” says Bournique, “this could help guide more precise treatment combinations for patients whose tumours are most likely to respond.”

Source: University of California - Irvine