Mutations in the ARID1a gene, which are common in many cancer types, disrupt DNA damage repair in cancer cells, allowing the cancer to progress. But this mutated gene may also strengthen specific cancer drugs’ ability to treat certain tumors, according to a team of MD Anderson researchers.
Their study, published in Cancer Discovery, discovered that certain mutations in ARID1a sensitize some tumors to PARP inhibitor drugs, such as olaparib, veliparib and BMN673, which block DNA damage repair pathways.
“Our results showed, particularly in the ARID1a deficient cells, PARP inhibitors are more effective than in other cancer cells,” says Guang Peng, M.D., Ph.D., assistant professor, Clinical Cancer Prevention, and senior author of the study. “Based on the mechanism we’ve discovered, we propose a new approach for targeting these mutant cancer cells.”
ARID1a is a component of the SWI/SNF complex, a group of proteins that work to rearrange the structure that organizes DNA, known as chromatin. This complex is also important for reorganizing this structure when DNA is damaged, so that cellular machinery can make repairs. When ARID1a is lost or mutated, cancer cells lose some ability to sense and correct DNA damage.
In this study the team identified, for the first time, the precise mechanism by which ARID1a plays a role in DNA damage response. Their findings revealed that it interacts with ATR, a protein with well-known roles in damage repair, and helps organize the DNA structure at the damage site.
Without normal ARID1a function, DNA damage repair is not performed as efficiently, and cancer cells are more sensitive to therapies that further disrupt critical repair pathways, such as PARP inhibitors. Using cancer cell lines as well as mouse models, the team showed that PARP inhibitors are significantly more effective at killing tumor cells with ARID1a loss or mutation.
The findings add ARID1a to a group of genes including BRCA1 and BRCA2 that confer a selective lethality to PARP inhibitors when mutated.
Read the full press release on the MD Anderson website.