UC Irvine Researchers Uncover New Clues to How Cancer Cells Respond to Treatment

A recent study by UC Irvine researchers identifies a potential biomarker for predicting a tumor’s drug response, moving us one step closer to personalized cancer treatment. 

“The study addresses an important challenge in cancer treatment: understanding which tumors will respond to drugs that interfere with DNA protection and repair,” says Rémi Buisson, PhD, an associate professor of biological chemistry at the UC Irvine School of Medicine. 

Working with colleagues at UC Irvine, in partnership with radiation oncologists from the University of Texas Health and Science Center, Buisson studied cellular responses to chemotherapy drugs that induce DNA damage. In particular, the team explored ATR, an enzyme that protects DNA and promotes its repair. 

“ATR inhibitors are being investigated in clinical trials as cancer treatments, alone and in combination with other drugs,” explains Buisson. “Identifying the biological features that influence ATR inhibitor response in cancer could help guide which patients should be treated with this cancer-targeting drug.” 

The team discovered that drugs blocking ATR can shut down protein production only in cancer cells that produce another enzyme called APOBEC3B. 

“Our experiments identify APOBEC3B as a key factor determining how cancer cells respond to ATR inhibitors,” says Buisson. The researchers share their findings in a paper published on Nov. 6, 2026, in Molecular Cell. 

When Genetic Messages Get Trapped 

When ATR is blocked, APOBEC3B can act on unprotected DNA, triggering a chain of events that causes aberrant activation of a DNA repair protein called PARP1. 

“We found that this overactive PARP1 traps messenger RNA inside the nucleus of the cells,” says Buisson, explaining that messenger RNAs are copies of instructions from DNA that cells use to make proteins. These messages must leave the nucleus to reach the machinery that makes proteins. 

“As a result, cancer cells can activate genes in response to treatment but fail to produce the corresponding proteins,” says Buisson. In other words, the instructions are written, but they cannot be delivered. 

This unexpected consequence of ATR inhibition disrupts the delivery system that allows cells to turn genetic instructions into proteins. “Proteins form the cell’s structures and machinery and control essential functions, including growth, DNA repair and responses to stress,” says Buisson. “Interrupting their production could therefore have important consequences for how cancer cells respond to treatment.” 

The study was conducted as part of a $3.1 million National Institutes of Health (NIH) grant, “Mechanisms and Functional Roles of PARP1 Hyperactivation in Cancer.” The work aims to elucidate the mechanism by which ATR inhibitors enhance cancer cell sensitivity to PARP inhibitors. 

Identifying a New Biomarker 

The study shows why measuring which genes are activated may tell only part of the story. 

Researchers often examine RNA levels to understand a cancer cell’s response to a drug. Yet a cell can produce large amounts of an RNA message while making very little of its protein because that message is trapped inside the nucleus.

 “A cancer cell may therefore appear to be mounting a strong response to treatment while failing to produce many of the proteins needed to carry it out,” says Buisson. Understanding this gap gives researchers a new way to investigate the effects of ATR inhibitors and how those effects differ between tumors. 

“In the cell models we tested, cancer cells producing APOBEC3B could activate the PARP1-dependent shutdown of protein production, whereas cells lacking APOBEC3B did not,” says Buisson. APOBEC3B is an enzyme highly expressed in many types of cancer cells. “This makes APOBEC3B a potential biomarker for identifying tumors likely to respond to cancer therapies using ATR inhibitors.” 

The team plans to test whether APOBEC3B can predict this response to ATR inhibitors in models that more closely reflect human tumors. “We want to establish how reliably its presence identifies cancer cells that undergo RNA trapping and reduced protein production,” says Buisson. 

They also need to determine what this shutdown means for treatment effectiveness. “It may help damaged cells recover, contribute to their death or have different effects, depending on the treatment conditions,” says Buisson. “Answering these questions will help us investigate whether APOBEC3B can guide the selection of treatments and drug combinations.” 

They also want to understand how combining ATR inhibitors with drugs that affect PARP1 changes protein production and cancer cell survival. 

“The next step is to determine whether this understanding can improve predictions of treatment benefit and help develop more effective approaches to cancer care,” says Buisson.

— Shani Murray