PARP Inhibitor Drugs Found to Have Hidden Talent

Designed to subvert tumor cells from within, a growing number of cancer drugs have also been found to have other talents. In the last few years, scientists have discovered that targeted drugs known as CDK4/6 inhibitors and certain chemotherapy agents not only hamper the internal workings of cancer cells but can also make them the prey of an immune system attack.

A new study in Cancer Discovery by Dana-Farber scientists adds another class of drugs to the list: PARP inhibitors.

Like all targeted therapies, PARP inhibitors work by impeding a specific aspect of cancer cell life — in this case, a pathway that repairs certain kinds of DNA damage. In cancer cells that already have a DNA-repair problem — because of a mutation in the BRCA genes, for example — the loss of a second repair pathway can doom the cells. In 2014, olaparib became the first PARP inhibitor to gain U.S. Food and Drug Administration approval for treating advanced ovarian cancers that carry a BRCA mutation; in 2018, it was approved for patients with metastatic breast cancer who have inherited BRCA mutations.

The findings

In the new paper, Dana-Farber researchers and their colleagues found that in triple-negative breast cancer, treatment with olaparib lures legions of immune system CD8⁺ T cells inside the tumor, where they wage battle against it. The investigators traced the chain of events, within the cancer cells and the surrounding tissue, that sets the attack in motion.

“Our results indicate that the anti-cancer effect of PARP inhibitors is two-pronged,” says Geoffrey Shapiro, MD, PhD, director of Dana-Farber’s Early Drug Development Center, a co-senior author of the study with Dana-Farber’s Jennifer Guerriero, PhD, and Gerburg Wulf, MD, PhD, of Beth Israel Deaconess Medical Center. “The loss of a DNA-repair pathway weakens tumor cells internally and exposes them to a powerful immune response at the same time.”

Previous studies were divided on whether PARP inhibitors recruited T cells to attack tumors. The new study focused on triple-negative breast cancer to help resolve the issue. Named for the absence of three cell-surface proteins, triple-negative breast cancer accounts for 10-20% of all breast cancer cases and often has a poor prognosis. Patients whose triple-negative breast cancer harbors a BRCA mutation often respond better to PARP inhibitors than to standard chemotherapy but eventually become resistant to the drugs and have their disease return.

Shapiro and his associates found that in animal models of triple-negative breast cancer with non-working BRCA and TP53 genes, treatment with olaparib prompted CD8⁺ T cells — professional killers of cancer cells — to infiltrate the tumor tissue. When researchers depleted the number of CD8⁺ T cells within the tumor, the anti-cancer effect declined, evidence that much of olaparib’s success against cancer lies in its ability to spark an immune response.

The investigators then explored how olaparib achieves this effect. One possibility was that tumor cells whose DNA-repair machinery was sputtering because of olaparib treatment would develop more genetic mutations and lift more cancer-related proteins, called neoantigens, to their surface. That, in turn, would draw an immune response. However, previous studies hadn’t indicated that that wasn’t the case with long-term exposure to PARP inhibitors.

Instead, as co-first author Constantia Pantelidou, PhD, of Dana-Farber, explains, “The accumulation of DNA damage within the cells activated the cGAS/STING pathway, which causes the cells to release proinflammatory cytokines [immune-signaling molecules]. That, in turn, activates dendritic cells,” immune system cells that attract T cells to the site of the tumor.

Proof of the critical role of cGAS/STING in this process came when researchers shut it down in cancer cells. This brought a halt to proinflammatory signaling, and to T-cell infiltration of the tumor tissue.

The discovery that PARP inhibitors work, in part, by triggering an immune response suggests that combining them with drugs known as immune checkpoint inhibitors may make them even more effective, researchers say. Studies are under way to determine if that is the case.