Preclinical study suggests ARID1a may be useful biomarker for immunotherapy

May 7, 2018, University of Texas M. D. Anderson Cancer Center
Guang Peng, M.D., Ph.D. Credit: MD Anderson Cancer Center

Functional loss of ARID1a, a frequently mutated tumor suppressor gene, causes deficiencies in normal DNA repair and may sensitize tumors to immune checkpoint blockade therapies, according to researchers from The University of Texas MD Anderson Cancer Center. The preclinical study suggests that mutations in ARID1a could be beneficial in predicting immunotherapy success.

The findings, published today in Nature Medicine, are the first to identify a role for ARID1a in regulating mismatch repair (MMR), a normal process for correcting DNA damage. Further, the study showed that treatment with immune checkpoint inhibitors targeting PD-1 successfully reduced burden and prolonged survival in mouse models with ARID1a-deficient tumors relative to controls.

Mutations in ARID1a occur frequently in a wide spectrum of cancers, with particularly high mutation rates (15-50 percent) in clear cell ovarian cancer, endometrial cancer, gastric cancer and bladder cancer. However, most mutations lead to loss of ARID1a, making it a poor therapeutic target, explained senior author Guang Peng, M.D., Ph.D., associate professor of Clinical Cancer Prevention.

"Since this is a very highly mutated gene in cancer, we wanted to better understand the biological function of ARID1a and potential therapeutic vulnerabilities," said Peng. "We did a variety of molecular assays and demonstrated, for the first time, that ARID1a deficiency has a causative relationship with MMR deficiency."

The researchers performed a screen in cancer cells to identify proteins which interact with ARID1a and discovered a connection with MSH2, a protein with a key role in regulating MMR. Additional in vitro assays confirmed that ARID1a was essential to normal MMR function.

Tumors with deficiencies in MMR are known to accumulate large numbers of genetic mutations and corresponding mutant proteins, or neoantigens, as the disease progresses. These neoantigens are thought to stimulate an immune response, making them more susceptible to checkpoint blockade therapy.

The researchers therefore analyzed data across cancer types from The Cancer Genome Atlas (TCGA) and confirmed that tumors with ARID1a mutations indeed carried higher mutational loads. Further, ARID1a mutations were more common in tumors with microsatellite instability (MSI), another marker for MMR dysfunction.

"The FDA has approved MMR deficiency as a marker for the use of checkpoint-blockade immunotherapy," said Peng. "Therefore, we wondered whether ARID1a-deficient tumors would have increased sensitivity to checkpoint blockade because they have impaired MMR and increased mutation load."

Further analysis of TCGA data revealed that tumors with ARID1a mutations exhibited an activation of the immune system, according to gene expression levels of immune markers. Therefore, the researchers investigated the use of checkpoint blockade inhibitors in treating tumors with ARID1a mutations.

Using mouse models of both ovarian and colorectal cancer, the researchers compared the effectiveness of anti-PD-1 therapy in mice with ARID1a-mutant tumors relative to controls with functional ARID1a. Treatment with the checkpoint blockade therapy significantly improved survival in mice with ARID1a mutations, suggesting immunotherapy could be useful for patients with ARID1a-mutant tumors.

"Our findings link ARID1a mutations to MMR deficiency, thus providing a therapeutic target by immune checkpoint blockade," said Peng. "We hope that our data will contribute to clinical studies testing ARID1a as a new biomarker for checkpoint blockade therapies."

Future work will be necessary to confirm the researchers' findings in clinical patient samples. Peng hopes to initiate clinical studies to investigate the value of ARID1a across types as a predictor of response to inhibitors targeting PD-1.

Explore further: Repurposing existing FDA-approved inhibitors may provide new treatment approach for ovarian cancer

Related Stories

Repurposing existing FDA-approved inhibitors may provide new treatment approach for ovarian cancer

March 27, 2018
Wistar researchers have found rationale for repurposing a class of antitumor compounds called HDAC inhibitors, already approved by the FDA for the treatment of diseases such as leukemia, as a new therapeutic option for ovarian ...

Study finds gene mutations sensitize tumors to specific cancer drugs

June 11, 2015
Mutations in ARID1a, which are common in many cancer types, disrupt DNA damage repair in cancer cells, allowing the cancer to progress. This gene may also be an Achilles' heel when treating certain tumors, according to a ...

Precancerous colon polyps in patients with Lynch syndrome exhibit immune activation

April 16, 2018
Colon polyps from patients with Lynch syndrome, a hereditary condition that raises colorectal cancer risk, display immune system activation well before cancer development, according to research from The University of Texas ...

New therapeutic approach for difficult-to-treat subtype of ovarian cancer identified

July 24, 2017
A potential new therapeutic strategy for a difficult-to-treat form of ovarian cancer has been discovered by Wistar scientists. The findings were published online in Nature Cell Biology.

Gene test could pinpoint patients sensitive to new type of cancer drug

December 22, 2016
Testing for a gene commonly mutated in ovarian cancers could pick out patients who will respond well to a promising new class of cancer drugs, a major new study reveals.

Loss of ARID1A protein drives onset and progress of colon cancer

December 12, 2016
A team of scientists has developed a model system in mice that allows them to look closely at how a protein often mutated in human cancer exerts its tumor-silencing effects. Not all cancers are caused by direct changes in ...

Recommended for you

Researchers uncover immune cell dysfunction linked to photosensitivity

August 16, 2018
Researchers at Hospital for Special Surgery (HSS) have discovered that a type of immune cell known as Langerhans appears to play an important role in photosensitivity, an immune system reaction to sunlight that can trigger ...

Chemicals found in vegetables prevent colon cancer in mice

August 14, 2018
Chemicals produced by vegetables such as kale, cabbage and broccoli could help to maintain a healthy gut and prevent colon cancer, a new study from the Francis Crick Institute shows.

Researchers artificially generate immune cells integral to creating cancer vaccines

August 14, 2018
For the first time, Mount Sinai researchers have identified a way to make large numbers of immune cells that can help prevent cancer reoccurrence, according to a study published in August in Cell Reports.

Doctors may be able to enlist a mysterious enzyme to stop internal bleeding

August 14, 2018
Blood platelets are like the sand bags of the body. Got a cut? Platelets pile in to clog the hole and stop the bleeding.

Team finds missing immune cells that could fight lethal brain tumors

August 13, 2018
Glioblastoma brain tumors can have an unusual effect on the body's immune system, often causing a dramatic drop in the number of circulating T-cells that help drive the body's defenses.

The medicine of the future against infection and inflammation?

August 13, 2018
Researchers at Lund University in Sweden, have in collaboration with colleagues in Copenhagen and Singapore, mapped how the body's own peptides act to reduce infection and inflammation by deactivating the toxic substances ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.