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

Author

• Md Arafat Khan, University of Nebraska Medical CenterFollow

ORCID ID

0000-0002-1861-5594

Graduation Date

Fall 12-19-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Biochemistry & Molecular Biology

First Advisor

Mohd Wasim Nasser

Abstract

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: Rb^fl/fl; Tp53^fl/fl; LSL-Myc^T58A) 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.

Comments

2025 Copyright, the authors

Rights

The author holds the copyright to this work and any reuse or permissions must be obtained from the author directly.

Recommended Citation

Khan, Md Arafat, "Targeting FOXM1/Aurora Kinase B Axis Attenuates Small Cell Lung Cancer Growth, Metastasis and Chemoresistance" (2025). Theses & Dissertations. 988.
https://digitalcommons.unmc.edu/etd/988