Rho-Kinase Inhibition By Fasudil Promotes Tumor Maturation And Apoptosis In Small-Cell Lung Cancer

Small-cell lung cancer (SCLC) is a poorly differentiated neuroendocrine neoplasm with inadequate therapeutic options. Fasudil is a Rho-associated protein kinase 1 and 2 (ROCK1/2) inhibitor whose clinical indications remain limited in cardiocerebrovascular diseases. This study aimed to report a possible implication of Fasudil for SCLC. The expression and prognostic value of ROCK1/2 were investigated immunohistochemically in surgical specimens. The positive rates of ROCK1 (77/113, 68.1%) and ROCK2 (94/113, 83.2%) were distinctly higher in SCLC than in other lung neuroendocrine tumors. The high expression level of ROCK1 was related to the poor long-term survival of patients, especially in the classic SCLC subtype. In vitro, SCLC cell line treated with Fasudil exhibited synapse-like morphologic change, accompanied by a reduction in the expression levels of c-myc and cyclin D1. Cell cycle arrest was further demonstrated, accompanied by sensitivity to starvation-induced apoptosis, indicating tumor maturation. In addition, RNA-seq identified hundreds of differentially expressed genes involved in the positive regulation of neuron differentiation, stem cell differentiation, cell development, and nervous system development. Finally, Fasudil inhibited SCLC growth, promoted structural maturity, and induced apoptosis in BALB/c nude mice xenograft model. In conclusion, these results indicated a potential and novel application of Fasudil for SCLC treatment.