According to a recent study published in the journal Cancer Discovery conducted by researchers at The University of Texas MD Anderson Cancer Center, mutations in ARID1a, common variations in many types of cancer, are responsible for the disruption of DNA damage repair in cancer cells, allowing the progression of cancer. In the study, the researchers also found that this gene may also be implicated in disruption of the treatment of certain tumors.
The researchers were able to determine that specific mutations in ARID1a (AT-rich interactive domain-containing protein 1a), a gene associated with the progression of cancer, induce certain tumors to PARP inhibitor drugs. These drugs include BMN673, olaparib and veliparib and the researchers found that mutations in the gene block the DNA damage repair pathways.
“Our results showed, particularly in the ARID1a deficient cells, PARP inhibitors are more effective than in other cancer cells,” said in a news release 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.”
The ARID1a gene has been found to be mutated in many types of cancer, particularly in a subset of ovarian cancer called clear cell carcinoma. In clear cell carcinomas, more than 50% of the tumors contain genetic mutations. High rates of ARID1a mutations are also present in hepatocellular carcinoma, uterine endometrioid carcinoma, breast cancer, gastric cancer among others.
ARID1a belongs to the SWI/SNF complex, a group of proteins that rearranges the DNA called chromatin. The SWI/SNF complex also reorganizes the DNA structure when this is damaged. When the it is absent or mutated, cancerous cells lose the ability repair the damage in the DNA. For the first time, researchers were able to identify the process by which ARID1a plays a role in the response to DNA damage. The researchers discovered that the gene interacts with the protein ATR, known to play a role in the repair of DNA damage, helping the DNA to restructure its features.
If the ARID1a gene is not functioning properly, the repair of the DNA damage is not efficient, making cancerous cells more sensitive to treatments that disrupt the pathways involved in the repair including the PARP inhibitors. The researchers used mouse models cancer lines and found that these inhibitors are more effective in destroying cancer tumor cells with ARID1a loss or mutation.
Results from this study add ARID1a to the evidence of genes (including the BRCA1 and BRCA2), that when mutated reduce the effectiveness of PARP inhibitors. According to the researchers, these results could potentially lead to the development of treatments especially for patients with clear cell carcinoma where traditional therapies are not as effective as in other subtypes of ovarian cancer. These findings also highlight the use of genomic information to guide cancer therapy and for the identification of personalized treatments.
“We need to identify which regions of this protein are critical for DNA damage response and repair, as not all patients with ARID1a mutations will be sensitive to PARP inhibitors,” said Peng. The team will now work in the classification of those genetic mutations and also on the identification of ways to target as cells with ARID1a mutations.