HOUSTON—It's well known that mutations in certain genes are hallmarks of cancer, but new research out of The University of Texas MD Anderson Cancer Center has found that in some cases, they can also improve cancer treatment effectiveness. The study, titled “ARID1a Deficiency Impairs the DNA Damage Checkpoint and Sensitizes Cells to PARP Inhibitors,” was published in Cancer Discovery.
AT-rich interactive domain-containing protein 1a (ARID1a) is part of a chromatin remodeling complex, and mutations of this gene disrupt DNA damage repair in cancer cells, enabling disease progression. However, other mutations of ARID1a can make tumors more sensitive to PARP inhibitor drugs such as olaparib, veliparib and BMN673, which block DNA damage repair pathways.
Dr. Guang Peng, assistant professor, Clinical Cancer Prevention, and senior author of the study, explains that ARID1a is part of the SWI/SNF chromatin remodeling complex, which plays a crucial role in rearranging chromatin to facilitate DNA repair.
Given how tiny the nucleus of a cell is, our DNA must be folded to fit, and in that process “it forms chromatin; that's the physical storage form of our genetic information,” says Peng. However, she notes, “That means when you need to express some gene, like a response to cell stress or cell growth, it's going to be very difficult for the transcription of this gene to be conducted in this very condensed chromatin environment.”
“Originally, people recognized that this chromatin remodeling is not only involved in controlling gene expression, it's also involved in controlling DNA repair,” Peng continues. “If you have damage in the DNA, the cell needs to repair that damage, but if the damage is in such a highly condensed chromatin structure, it's very difficult to repair because other proteins cannot go there to fix the damage. This chromatin remodeling complex will participate in the DNA damage site and relax the environment to create a favorable environment for the DNA repair and the DNA damage response.”
The exact role ARID1a plays in DNA damage response was identified in this study, as the researchers reported that ARID1a interacts with ATR, a protein that plays a role in damage repair, and helps to organize the DNA structure at the site of the damage. When ARID1a is not functioning normally, DNA damage repair is less efficient, which allows the cancer to progress but also makes cancer cells more sensitive to therapies such as PARP inhibitors that specifically disrupt critical repair pathways. In both cancer cell lines and mouse models, PARP inhibitors were shown to be significantly more effective at killing tumors that presented with ARID1a mutation or loss. Specifically, the authors note in the study's abstract that “ARID1A is recruited to DNA double-strand breaks (DSB) via its interaction with the upstream DNA damage checkpoint kinase ATR. At the molecular level, ARID1A facilitates efficient processing of DSB to single-strand ends and sustains DNA damage signaling. Importantly, ARID1A deficiency sensitizes cancer cells to PARP inhibitors in vitro and in vivo, providing a potential therapeutic strategy for patients with ARID1A-mutant tumors.”
Not all mutations of this gene affect its functions in the same way, however, and as such, Peng noted that “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.”
The next steps for this research will be to determine which mutations confer PARP inhibitor sensitivity and to explore other ways to selectively target cells with ARID1a mutations or mutations in other genes within the SWI/SNF complex. Peng says the team would like to investigate how specific mutations will change the response to PARP inhibitors. Additionally, she tells DDNews, “not one single tumor cell has only one mutation in ARID1a; it does have other genetic alterations coexisting with ARID1a mutation. So how those mutations are going to change the response to PARP inhibitors and how we can maybe target an adaptive response in ARID1a-deficient cells to improve the effect are two questions we would like to follow up.” Peng adds that they have seen some interest to conduct clinical trials based on this study.
While ARID1a is mutated in many cancer types, it is the most commonly mutated gene in a type of ovarian cancer known as clear cell carcinoma, with over 50 percent of tumors containing gene alterations. ARID1a is also seen to have a high rate of mutation in uterine endometrioid carcinoma, gastric cancer, hepatocellular carcinoma and breast cancer, among others.