Preclinical study could help lead to better treatments for LKB1-deficient lung cancer
A new study by researchers at the UCLA Jonsson Comprehensive Cancer Center have identified a novel combination therapy to potentially help overcome resistance to immunotherapy in people diagnosed with advanced lung cancer.The combination approach uses immune checkpoint inhibitors with ATRA, a safe medication that is widely used to treatleukemia. The team found the combination therapy lead toeradication of over 70% of tumors when tested in mice with LKB1-deficient lung cancer. It also generated durable tumor-specific immunity.
Immune checkpoint inhibitors have substantially improved the outcomes for people with lung cancer. The five-year survival rate for patients with advanced disease on this therapy is more than 13% compared to 5% in patients with conventional chemotherapy. Although immunotherapy has been successful for many patients, a majority of patients still do not respond to the therapy.
To help increase the number of patients who benefit from this therapy, researchers have sought to identify mechanisms for treatment resistance. The tumor suppressor gene LKB1 are found mutated in 20% of patients with non-small cell lung cancer and 30% of KRAS-mutant non-small cell lung cancers. It also is a major gene associated with resistance to immune checkpoint inhibitors. By identifying aberrant pathways caused by LKB1 mutation, researchers are figuring out a novel therapy that targets the pathway and sensitizes LKB1-deficient tumors to immunotherapy.
To assess the response of the combination therapy, researchers tested the therapy in mice that were injected with LKB1-deficient lung tumors.
The study provides evidence that using ATRA in combination with checkpoint inhibitors could potentially help patients with advanced lung cancer who carry LKB1 mutation to have a positive response to immunotherapy.
Lead authors are Rui Li, MD, PhD, currently a resident physician of internal medicine at UCLA, and Ramin Salehi-Rad, MD, PhD, a physician scientist in pulmonary and critical caremedicine. The senior authors are Bin Liu, PhD, an adjunct professor of pulmonary and critical care medicine, and Steven Dubinett, MD, a professor of pulmonary and critical care medicine, pathology and laboratory medicine, and molecular and medical pharmacology at the Geffen School of Medicine and physician-scientist in the UCLA Jonsson Comprehensive Cancer Center.
The study was published online in Cancer Research, a journal of the American Association for Cancer Research.
The research was supported in part by funding from the National Cancer Institute, the National Heart Lung and Blood Institute and the Department of Veteran Affairs.
Featured image: UCLA cancer researcher Rui Li © UCLA
Reference: Rui Li, Ramin Salehi-Rad, William Crosson, Milica Momcilovic, Raymond J. Lim, Stephanie L. Ong, Zi Ling Huang, Tianhao Zhang, Jensen Abascal, Camelia Dumitras, Zhe Jing, Stacy J. Park, Kostyantyn Krysan, David B. Shackelford, Linh M. Tran, Bin Liu and Steven M. Dubinett, “Inhibition of Granulocytic Myeloid-Derived Suppressor Cells Overcomes Resistance to Immune Checkpoint Inhibition in LKB1-deficient Non-Small Cell Lung Cancer”, Cancer Research, 2021. DOI: 10.1158/0008-5472.CAN-20-3564
Provided by UCLA