Researchers at the Icahn School of Medicine at Mount Sinai have identified the mechanism of action of a treatment for small-cell lung cancer (SCLC), one of the most aggressive and difficult-to-treat cancers. Published this week in Cell Reports Medicine, the study reveals that the drug lurbinectedin, an approved second-line therapy for SCLC, activates the STING-IFN signalling pathway to enhance the immune response against tumours.

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

Senior and corresponding author Triparna Sen, Ph.D., is Associate Professor of Oncological Sciences, and Director of the Lung Cancer PDX Platform, at the Icahn School of Medicine at Mount Sinai. Her team, including postdoctoral fellow Subhamoy Chakraborty, Ph.D., who led the work in the lab, uncovered how lurbinectedin, approved by the Federal Drug Administration in 2020, activates the STING pathway, a critical immune-signalling pathway.

STING signaling is an innate immune signaling which then leads to the upregulation of the IFN signaling. IFN expression is downstream of STING signaling. This activation enhances the production of interferons and pro-inflammatory chemokines, and promotes the expression of the major histocompatibility complex class I (MHC-I) protein, which is essential for immune cells to recognise and attack cancer cells.

The team, which also included Ph.D. students Subhasree Sridhar and Konrad Snioch and several members of the BINGs team, demonstrated that lurbinectedin's immune-modulatory effects could significantly boost the efficacy of PD-L1 blockade therapies, providing new hope for patients with limited treatment options.

The Sen lab at the Icahn School of Medicine at Mount Sinai investigates the biology of recalcitrant subtypes of lung cancer to identify therapies for thoracic malignancies.

"Our study is the first to uncover the immune-enhancing properties of lurbinectedin," said Dr. Sen. "By activating the STING pathway, the drug promotes a robust anti-tumour immune response, improving outcomes in both first-line and maintenance therapy settings. This discovery could redefine the treatment landscape for extensive-stage SCLC."

The study's findings are especially timely, as recent clinical trials, such as the IMforte phase 3 study, demonstrated improved outcomes for SCLC patients when lurbinectedin was combined with the PD-L1 inhibitor atezolizumab (Tecentriq).

"These promising results provide further validation for the potential of combining lurbinectedin with immune therapies to enhance survival and quality of life for patients battling this aggressive disease," Dr. Sen said.