New findings reveal why only some cancers respond to ATR inhibitor therapy

Many cancer therapies damage the DNA of cancer cells and prevent repair, effectively stopping or slowing tumor growth. However, certain repair enzymes such as ATR can sense these damages and activate a “survival” response within the cancer cells. To counter this, ATR inhibitors are currently being tested in clinical trials, showing some, but not universal, success. To gain a better understanding of why ATR inhibitors are effective against some cancers but not others, UC Irvine researchers conducted a study to determine how cancer cells respond to ATR inhibitor treatment.

“We wanted to understand why certain types of cancer cells are highly sensitive to drugs that inhibit the ATR enzyme, while other cancer cells respond poorly to this treatment,” says Rémi Buisson, PhD, an associate professor of biological chemistry in UC Irvine’s School of Medicine. “A better understanding of which types of cancer cells are more sensitive to ATR inhibition and the underlying reasons for this sensitivity will greatly improve personalized treatment strategies by identifying specific biomarkers that can predict patient response.”

The researchers outline their findings in a paper, “Mechanism of DNA Replication Fork Breakage and PARP1 Hyperactivation During Replication Catastrophe,” published in the journal Science Advances. Their mechanistic insight into how ATR inhibition triggers cell death in cancer cells suggests a new approach for predicting treatment success.

“We found that ATR inhibition disrupts DNA replication, leading to the formation of unprotected DNA regions that become targeted by the DNA deaminase enzyme APOBEC3B,” says Buisson. “APOBEC3B-mediated DNA deamination initiates a cascade of events resulting in DNA cleavage and the accumulation of DNA double-strand breaks, ultimately causing cell death.”

More importantly, the team discovered that different cancer cells express varying levels of APOBEC3B, and that the expression level of APOBEC3B correlates with the cells’ sensitivity to ATR inhibitors.

“The expression level of APOBEC3B is a key determinant of cancer cell sensitivity to ATR inhibitors,” says Pedro Ortega, a postdoctoral fellow in the Buisson Laboratory and first author of this study. “These findings suggest that measuring APOBEC3B levels in cancer cells could be used to predict how a patient’s tumor will respond to ATR inhibitor treatment.”

This work was supported in part by funding from the National Institutes of Health (NIH) and the American Cancer Society. Other funders included the California Institute for Regenerative Medicine, the European Molecular Biology Organization, the Pershing Square Sohn Cancer Research Alliance, the Department of Defense, and Pedal the Cause.