Targeting FOXM1 reshapes antitumor immunity to attenuate small cell lung cancer progression

Md Arafat Khan; Parvez Khan; Mahek Fatima; Asad Ur Rehman; Laiba Anwar; Zahraa Wajih Alsafwani; Aatiya Ahmad; Mohammad Ali Abbas Zaidi; Jesse L Cox; Areem Zahid; Sameer Mohiuddin; Sung Hoon Kim; Juan A Santamaria-Barria; Imayavaramban Lakshmanan; Benita S Katzenellenbogen; John A Katzenellenbogen; Apar K Ganti; Surinder K Batra; Mohd Wasim Nasser

doi:10.1016/j.canlet.2025.218160

Targeting FOXM1 reshapes antitumor immunity to attenuate small cell lung cancer progression

Cancer Lett. 2026 Jan 28:638:218160. doi: 10.1016/j.canlet.2025.218160. Epub 2025 Nov 21.

Authors

Md Arafat Khan¹, Parvez Khan², Mahek Fatima¹, Asad Ur Rehman¹, Laiba Anwar¹, Zahraa Wajih Alsafwani¹, Aatiya Ahmad¹, Mohammad Ali Abbas Zaidi¹, Jesse L Cox³, Areem Zahid¹, Sameer Mohiuddin¹, Sung Hoon Kim⁴, Juan A Santamaria-Barria⁵, Imayavaramban Lakshmanan¹, Benita S Katzenellenbogen⁶, John A Katzenellenbogen⁴, Apar K Ganti⁷, Surinder K Batra⁸, Mohd Wasim Nasser⁹

Affiliations

¹ Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE-68198, USA.
² Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE-68198, USA. Electronic address: parvez.khan@unmc.edu.
³ Department of Pathology, Microbiology and Immunology, University of Nebraska Medical Center, Omaha, NE-68198, USA.
⁴ Department of Chemistry and Cancer Center, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
⁵ Department of Surgery, University of Nebraska Medical Center, Omaha, NE, USA.
⁶ Department of Molecular and Integrative Physiology and Cancer Center, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
⁷ Division of Oncology-Hematology, Department of Internal Medicine, VA-Nebraska Western Iowa Health Care System, And Division of Oncology-Hematology, University of Nebraska Medical Center, Omaha, NE-68198, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE-68198, USA.
⁸ Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE-68198, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE-68198, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE-68198, USA.
⁹ Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE-68198, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE-68198, USA. Electronic address: wasim.nasser@unmc.edu.

PMID: 41276109
DOI: 10.1016/j.canlet.2025.218160

Abstract

Small cell lung cancer (SCLC) is a lethal lung malignancy, which is associated with distant metastasis and chemoresistance. Due to the limited availability of targeted therapies, identifying a potential therapeutic target is a pressing unmet need in SCLC. Single-cell and bulk-transcriptomic datasets were analyzed that revealed FOXM1 as a potential targeting candidate in SCLC. High FOXM1 expression was observed in human and murine SCLC tissues and cell lines. Interestingly, chemoresistant (CR) SCLC cells exhibited substantially higher FOXM1 expression compared to naïve SCLC. Furthermore, FOXM1 inhibition in combination with platinum-based chemotherapy showed synergistic anticancer effects in vitro and in vivo xenograft and spontaneous (RPM: RB1^fl/fl; TP53 ^fl/fl; LSL-MYCT58A) mouse models of SCLC. Mechanistically, RNA-seq analysis revealed that FOXM1 inhibition altered the Aurora Kinase B (AURKB) signaling pathway. Notably, FOXM1 inhibition enhanced T cell activation, supported differentiation of CD8⁺ T cells, and T cell-mediated killing of SCLC cells. Additionally, FOXM1 inhibition enhanced CD8⁺ T cell and macrophage recruitment in the tumor microenvironment (TME) of immunocompetent RPM model. This study demonstrates that FOXM1 targeting small molecule inhibitors (FOXM1i) has the potential to be a novel therapeutic strategy to combat SCLC progression, including chemotherapeutic resistance and reshaping the anti-tumor immune response.

Keywords: Chemotherapeutic resistance; FOXM1 inhibitors; Metastasis; Small cell lung cancer; T cell activation.

MeSH terms

Animals
CD8-Positive T-Lymphocytes / drug effects
CD8-Positive T-Lymphocytes / immunology
Cell Line, Tumor
Disease Progression
Drug Resistance, Neoplasm / drug effects
Forkhead Box Protein M1* / antagonists & inhibitors
Forkhead Box Protein M1* / genetics
Forkhead Box Protein M1* / metabolism
Gene Expression Regulation, Neoplastic / drug effects
Humans
Lung Neoplasms* / drug therapy
Lung Neoplasms* / genetics
Lung Neoplasms* / immunology
Lung Neoplasms* / pathology
Mice
Signal Transduction / drug effects
Small Cell Lung Carcinoma* / drug therapy
Small Cell Lung Carcinoma* / genetics
Small Cell Lung Carcinoma* / immunology
Small Cell Lung Carcinoma* / pathology
Tumor Microenvironment / drug effects
Tumor Microenvironment / immunology
Xenograft Model Antitumor Assays

Substances

Forkhead Box Protein M1
FOXM1 protein, human

Abstract

MeSH terms

Substances

Grants and funding