In their quest for effective targeted therapies to treat triple-negative breast cancer (TNBC) — an aggressive disease that often doesn’t respond to standard chemotherapy — researchers at Dana-Farber and elsewhere have recently focused on the potential of drugs known as BET bromodomain inhibitors.
BET inhibitors target a family of proteins including BRD2, BRD3, BRD4, and BRDT, which regulated the activity of cancer-causing oncogenes such as MYC various blood cancers and some solid tumors. BET proteins are also overexpressed in glioblastoma brain tumors and in melanoma.
A publication in 2010 described one of the first BET inhibitors, JQ1, which was developed at Dana-Farber by James Bradner, MD, and Jun Qi, PhD, and showed promising activity against a rare cancer, NUT midline carcinoma. While JQ1 and other BET inhibitors are being evaluated in several forms of cancer including breast cancer, Kornelia Polyak, MD, PhD, notes that tumors often are inherently resistant to BET inhibitors or rapidly develop acquired resistance. She says that because genomic studies have failed to find commonly mutated genes and proteins in triple-negative breast cancers and because the genetic makeup of these tumors is highly heterogeneous, combinations of agents will likely be required for effective treatment.
In a report in Molecular Cell, Polyak described the use of powerful combined functional and molecular profiling — including small molecule inhibitor and CRISPR gene editing screens — to study resistance and sensitivity to BET inhibitors in triple-negative breast cancer cells. They identified genes that when deleted cause the breast cancer cells to resist or potentiate BET inhibitor treatment, as well as combinations of BET inhibitors with various targeted and chemotherapeutic drugs that acted more potently in combination than as single agents to make triple-negative breast cancer cells more sensitive to treatment.
Among other findings, the study revealed positive synergies between BET inhibitors and inhibitors of CDK4 that regulate cell cycle progression, such as palbociclib, and between BET inhibitors and paclitaxel, a chemotherapeutic agent. Since both palbociclib and paclitaxel are already in use for treatment of breast cancer patients, these new combinations are relatively straightforward to test in the clinic. Thus, based on these and earlier findings, Polyak and her colleagues have designed clinical trials of these combinations that showed promise in the laboratory. These trials are currently being reviewed.