A newly identified form of BRCA1-associated protein-1 (BAP1) increases malignant pleural mesothelioma cells’ vulnerability to some cancer therapies, a study indicates.
The findings suggest a new strategy for treating patients carrying the protein. The study, “A novel BRCA1-associated protein-1 isoform affects response of mesothelioma cells to drugs impairing BRCA1-mediated DNA repair,” was published in the Journal of Thoracic Oncology.
Errors in the BAP1 gene that lead to a non-functional protein play a key role in the development of malignant pleural mesothelioma, research has indicated. BAP1 is a tumor suppressor, so its proper functioning is vital to the regulation of processes that, if uncontrolled, can lead to cancer development.
Researchers have discovered a previously unknown form of BAP1 in malignant pleural mesothelioma cell lines. BAP1delta is missing the catalytic domain present in other forms of the protein. The catalytic domain is the part of a protein where chemical reactions occur.
The research team set out to characterize the function of the BAP1delta protein and see if it had any therapeutic value.
They detected BAP1delta in standard mesothelioma cell lines in addition to malignant pleural mesothelioma lines. They also found greater expression of the protein in non-tumor than in tumor tissue.
In addition, the team discovered that BAP1delta was less functional than BAP1. Since BAP1 is a tumor suppressor, they concluded that the BAP1delta variant has less capacity to repair DNA damage.
When malignant pleural mesothelioma cells expressed a certain amount of BAP1delta in addition to the fully functional BAP1 protein, it made the cells more vulnerable to the killing effects of Lynparza (olaparib). That drug is an FDA-approved targeted therapy for ovarian cancer patients with BRCA mutations.
Adding Apitolisib (GDC-0980) to Lynparza in the same BAP1delta-expressing scenario made Lynparza even more effective, researchers said. The FDA has yet to approve Apitolisib, but a clinical trial shows it has cancer-fighting ability, especially in mesothelioma.
Overall, the results suggest that BAP1delta regulates cells’ DNA damage response and influences sensitivity to drugs.
A previous study found that 77 percent of patients with malignant pleural mesothelioma carry a fully functional BAP1 protein. This means that as many as 15 percent could be carrying BAP1delta. They could benefit from a combination of Lynparza and Apitolisib, researchers said.