BET inhibitor tamps down PD-L1 activity in ovarian cancer cells

Wistar Institute scientists have found a class of drugs that effectively dampened PD-L1 activity in ovarian cancer, even though it does not directly target PD-L1. Called bromodomain and extraterminal domain (BET) inhibitors, multiple candidates are in clinical trials for other cancers.

The interaction between the PD-1 protein and its ligand, PD-L1, blocks T cells from fighting tumor growth. But antibody-based drugs that disrupt this interaction can cause immune-related side effects, the scientists said in a statement.

"We wanted to explore anti-PD-L1 therapies specifically for ovarian cancer, but we also wanted to determine if other drugs that did not cause these negative anti-PD-L1 antibody-related side effects could be used to target this cancer-promoting pathway," said Rugang Zhang, lead author of the study and a professor at the Wistar Institute.

They came upon BET inhibitors in their search for small molecule inhibitors, which inhibit cancer progression by targeting cells with cancer-associated mutations or proteins without harming healthy cells. They tested the BET inhibitor JQ1 in epithelial ovarian cancer cell lines and found it effectively suppressed PD-L1 activity and tamped down inflammatory responses, according to the statement.

While BET inhibitors do not specifically target PD-1/PD-L1, they work because the BET protein BRD4 regulates the expression of PD-L1, the researchers said. In ovarian cancer, cells tend to express higher levels of the BRD4 gene, so it could also be used as a biomarker to select patients who could benefit from treatment with BET inhibitors.

Merck markets the PD-1 drug Keytruda, while Bristol-Myers Squibb markets Opdivo. In July, Pfizer and Merck KGaA kicked off a Phase III trial combining a PD-L1 drug and platinum-based chemotherapy in epithelial ovarian cancer. Meanwhile, BET inhibitors are in clinical trials for various cancers, including hematologic malignancies and NUT midline carcinoma.