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Publication of a paper clarifying the mechanism of action of PAI-1 inhibitor RS5614 in non-small cell lung cancer (inhibition of epithelial-mesenchymal transition (EMT), improvement of drug resistance, and improvement of the tumor immune microenvironment).
We are pleased to announce that the mechanism of action of our PAI-1 inhibitor RS5614 in immune checkpoint inhibitor-resistant non-small cell lung cancer has been elucidated in a collaborative study with the Hiroshima University Graduate School of Biomedical Sciences and the Tohoku University Graduate School of Medicine.
This paper was published in Molecular Cancer Therapeutics on November 6, 2025.
Standard first-line treatment for non-small cell lung cancer (NSCLC), which accounts for 85% of lung cancers, a leading cause of cancer-related deaths, consists of cytotoxic chemotherapy and immunotherapy using immune checkpoint inhibitors (ICIs) targeting PD-L1 (programmed cell death ligand 1) or PD-1. However, only a small proportion of patients are cured, and more than half experience cancer progression within one year of treatment initiation. One of the reasons for this is the development of resistance in cancer cells to cytotoxic chemotherapy and ICIs. This paper demonstrates that plasminogen activator inhibitor (PAI)-1 plays an important role in cancer cell resistance to ICIs. Furthermore, the PAI-1 inhibitor RS5614 reverses resistance, enhances ICI efficacy, and promotes tumor regression by activating tumor immunity.
In a mouse model implanted with non-small cell lung cancer cells, tumor growth was suppressed for up to seven days after ICI administration. However, tumors subsequently acquired resistance to ICIs and rapidly proliferated. Cancer cells resistant to ICIs were found to express significantly higher levels of PAI-1. Indeed, in human non-small cell lung cancer sections, higher levels of PAI-1 expression have been observed in patients treated with ICIs.
An important pathological condition in considering ICI resistance is epithelial-mesenchymal transition (EMT)2). EMT is a process in which cancer cells lose their original epithelial cell properties and acquire the properties of mesenchymal cells, which have high invasive and migratory properties. Cancer cells that have undergone EMT are more likely to survive in the presence of cytotoxic chemotherapy and ICIs, and are one of the major mechanisms for acquiring drug resistance. EMT is induced by cytotoxic chemotherapy and ICIs in many cancers, not just non-small cell lung cancer, and is a factor in the acquisition of treatment resistance.
Interestingly, EMT was induced in cancer tissue that had acquired resistance to ICIs, but administration of RS5614 was found to suppress EMT, resulting in an improvement in the tumor immune microenvironment (TIME)2) and activation of key immune responses, including activation of T lymphocytes, decrease in tumor-infiltrating macrophages, and reduced expression of ICs on cancer cells. This suggests the potential for RS5616 to be a therapeutic agent that can ameliorate the acquisition of resistance to cytotoxic chemotherapy and ICIs in a variety of cancers, and is considered to be an extremely important finding in cancer treatment.
We are conducting a Phase II clinical trial evaluating the efficacy and safety of the combination of nivolumab and RS5614 in patients with unresectable, advanced, or recurrent non-small cell lung cancer who have previously received multiple anticancer drug therapies. The trial began in September 2023 at Hiroshima University, Shimane University, Okayama University, Tottori University, Shikoku Cancer Center, and Hiroshima City Hospital (Clinical Trial Coordinator: Professor Noboru Hattori, Department of Respiratory Medicine, Hiroshima University Hospital). Patient enrollment has been completed (disclosed on June 30, 2025). After the treatment period, we plan to compile the results of the study evaluation and data analysis into a clinical trial report.
1) Epithelial-Mesenchymal Transition (EMT)
This is a phenomenon in which epithelial cells, which form tissue through cell-cell adhesion, transform into highly mobile mesenchymal cells. This is one of the triggers that promotes tissue fibrosis, cancer invasion, and metastasis.
2) Tumor Immune Microenvironment (TIME)
This refers to a tissue state that differs from normal tissue due to interactions between cancer cells and surrounding cells. Anticancer drugs make cancer cells less susceptible to immune attack, which is thought to be one of the factors that contribute to the acquisition of resistance.