Mount Sinai Study Reveals Immune-Modulatory Mechanism of Lurbinectedin in Small-Cell Lung Cancer
FDA-approved drug activates pathways enhancing immune response against tumors
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 signaling pathway to enhance the immune response against tumors.
Small-cell lung cancer is one of the most aggressive types of cancer. It represents about 10 to 15 percent 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 percent.
Senior and corresponding author Triparna Sen, PhD, 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, PhD, 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-signaling 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 recognize and attack cancer cells.
The team, which also included PhD students Subhasree Sridhar and Konrad Snioch and several members of the BINGs team, demonstrated that lurbinectedin's immune-modulatory effects can 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-tumor 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.
This study, titled “Lurbinectedin sensitizes PD-L1 blockade therapy by activating STING-IFN signaling in small cell lung cancer,” was supported by the National Institute of Health and Jazz Pharmaceuticals, and involved collaboration with Memorial Sloan Kettering Cancer Center and Moffitt Cancer Center.
About the Icahn School of Medicine at Mount Sinai
The Icahn School of Medicine at Mount Sinai is internationally renowned for its outstanding research, educational, and clinical care programs. It is the sole academic partner for the eight- member hospitals* of the Mount Sinai Health System, one of the largest academic health systems in the United States, providing care to New York City’s large and diverse patient population.
The Icahn School of Medicine at Mount Sinai offers highly competitive MD, PhD, MD-PhD, and master’s degree programs, with enrollment of more than 1,200 students. It has the largest graduate medical education program in the country, with more than 2,600 clinical residents and fellows training throughout the Health System. Its Graduate School of Biomedical Sciences offers 13 degree-granting programs, conducts innovative basic and translational research, and trains more than 500 postdoctoral research fellows.
Ranked 11th nationwide in National Institutes of Health (NIH) funding, the Icahn School of Medicine at Mount Sinai is among the 99th percentile in research dollars per investigator according to the Association of American Medical Colleges. More than 4,500 scientists, educators, and clinicians work within and across dozens of academic departments and multidisciplinary institutes with an emphasis on translational research and therapeutics. Through Mount Sinai Innovation Partners (MSIP), the Health System facilitates the real-world application and commercialization of medical breakthroughs made at Mount Sinai.
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* Mount Sinai Health System member hospitals: The Mount Sinai Hospital; Mount Sinai Beth Israel; Mount Sinai Brooklyn; Mount Sinai Morningside; Mount Sinai Queens; Mount Sinai South Nassau; Mount Sinai West; and New York Eye and Ear Infirmary of Mount Sinai.
About the Mount Sinai Health System
Mount Sinai Health System is one of the nation’s leading integrated academic health systems and one of the largest in the New York metropolitan area. Its comprehensive system includes seven hospitals, more than 400 outpatient practices, over 600 research and clinical laboratories, the Icahn School of Medicine at Mount Sinai, the Graduate School of Biomedical Sciences, and the Mount Sinai Phillips School of Nursing. Together, the Health System comprises approximately 48,000 employees, more than 9,000 physicians, and 8,600 nurses.
As a leading learning health system, Mount Sinai combines clinical expertise with scientific discovery to improve patient care while training the next generation of health care and biomedical leaders. The Health System provides care across every stage of life, from prenatal care through geriatrics, while advancing personalized medicine through artificial intelligence, data science, and biomedical research.
Mount Sinai is consistently recognized among the nation’s leading academic health systems for patient care, research, and education. The Mount Sinai Hospital is ranked No. 1 in New York by Newsweek and No. 5 on the magazine’s World’s Best Hospitals list. The Icahn School of Medicine at Mount Sinai ranks No. 11 among U.S. medical schools and No. 1 among freestanding medical schools for National Institutes of Health funding, reflecting the strength of its scientific enterprise and leadership in biomedical research.