Targeting FOXM1/Aurora Kinase B Axis Attenuates Small Cell Lung Cancer Growth, Metastasis and Chemoresistance

Small cell lung cancer (SCLC) is a deadly malignancy of the lung. Most SCLC patients show distant metastasis at the time of diagnosis, and consequently, the patients show dismal survival. Etoposide in combination with platinum-based chemotherapy has been used as the standard of care for SCLC patients for more than 30 years. This regimen shows a prominent anti-tumor response; however, nearly all patients encounter a disease relapse with inherent chemoresistance. The expeditious development of chemo-resistance causes SCLC patients to have a median overall survival of 12-16 months. Additionally, the lack of effective targeted therapies for SCLC has complicated the disease outcome. In search of promising molecular targets in SCLC, we analyzed publicly available single-cell RNA-sequencing (RNA-seq) data that revealed FOXM1 (Forkhead Box M1), an oncogenic transcription factor, is overexpressed in SCLC, which is recapitulated in SCLC tissues and cell lines. Interestingly, chemo-resistant SCLC showed a substantially higher level of FOXM1 expression relative to naive SCLC. Genetic silencing of FOXM1 or its targeting using pharmacological inhibitors revealed a substantial reduction in cell viability, colony formation, migration and sphere formation in naïve and chemo-resistant SCLC models. FOXM1 inhibition (by FDI-6 and NB-73) also induced cell cycle arrest and apoptosis in SCLC cells. Combining FOXM1 inhibitor with first-line chemotherapy showed synergistic anticancer effects in vitro as well as in xenograft and spontaneous mouse models (RPM: Rbfl/fl; Tp53fl/fl; LSL-MycT58A) of SCLC. Our RNA-seq studies revealed that FOXM1 inhibition significantly downregulated Aurora Kinase B signaling pathway, which is dysregulated in SCLC. Furthermore, we have found that FOXM1 inhibition enhances T cell activity and T cell-mediated killing of cancer cells. Altogether, these findings demonstrate that FOXM1 inhibition is a potential therapeutic strategy to combat SCLC.