by The Mount Sinai Hospital

ATR expression and the antitumor effect of ATRi in SCLC. Credit: Science Advances (2024). DOI: 10.1126/sciadv.ado4618

Researchers at the Icahn School of Medicine at Mount Sinai have made a promising breakthrough in the treatment of small cell lung cancer (SCLC). Their study, published in Science Advances and titled "ATR Inhibition Activates Cancer Cell cGAS/STING-Interferon Signaling and Promotes Anti-Tumor Immunity in Small Cell Lung Cancer," presents an exciting new approach that offers hope to patients with this challenging disease.

Small cell lung cancer is one of the most aggressive types of cancer. It represents about 10 to 15% of all lung cancer cases in the United States, with roughly 30,000 to 35,000 new cases each year. Unfortunately, by the time most patients are diagnosed, the cancer has often spread, making it difficult to treat. Current treatments, such as chemotherapy and immunotherapy, offer only temporary relief, and the five-year survival rate is less than 10%.

"We've concentrated on ATR (ataxia telangiectasia and Rad3-related protein), which plays a key role in repairing DNA in cancer cells. By inhibiting ATR, we make these cancer cells more vulnerable to treatments and enhance the immune system's ability to target them," said Triparna Sen, Ph.D., Associate Professor of Oncological Sciences, and the Director of the Lung Cancer PDX Platform, at Icahn Mount Sinai.

New treatment strategy: One-two punch

The study explored the effects of a new drug called berzosertib (M6620/VX970) combined with another drug, topotecan, to treat SCLC patients who have relapsed.

"Our findings suggest that this combination could be very effective, especially for patients whose cancer has returned," Dr. Sen noted. The research also suggests that using ATR inhibitors along with anti-PD-L1 antibodies, a type of targeted immunotherapy called an immune checkpoint inhibitor that helps the immune system recognize and attack cancer cells, might improve outcomes even further.

The study showed that inhibiting ATR activates a part of the immune system known as the cGAS-STING pathway. This leads to an increase in immune signals like interferons and chemokines, which help the immune system detect and attack cancer cells more effectively.

"We have previously established that DNA damage response proteins are effective targets for small cell lung cancer and this research, co-led by postdocs Hirokazu Taniguchi, MD, Ph.D. and Subhamoy Chakraborty, Ph.D., is a significant advancement in treating small cell lung cancer. By targeting ATR and enhancing the immune response, we are opening up new possibilities for better treatment options," Dr. Sen explained.

The Mount Sinai team plans to propose a clinical trial to test these new treatments by 2025. They hope this research will also benefit other hard-to-treat cancers.

More information: Hirokazu Taniguchi et al, ATR inhibition activates cancer cell cGAS/STING-interferon signaling and promotes antitumor immunity in small-cell lung cancer, Science Advances (2024). DOI: 10.1126/sciadv.ado4618

Journal information: Science Advances 

Provided by The Mount Sinai Hospital