Effective combination treatments for breast cancer inhibition by FOXM1 inhibitors with other targeted cancer drugs

• Published in: Breast cancer research and treatment 2023-04, Vol.198 (3), p.607-621
• Main Authors: Guillen, Valeria Sanabria, Ziegler, Yvonne, Gopinath, Chirag, Kumar, Sandeep, Dey, Parama, Plotner, Blake N., Dawson, Nadia Z., Kim, Sung Hoon, Katzenellenbogen, John A., Katzenellenbogen, Benita S.
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cancer research; Cancer therapies; Caspase 3 - genetics; Caspase-3; Cell cycle; Cell Line, Tumor; Cell Proliferation; Cell viability; Drugs; Female; Forkhead Box Protein M1 - genetics; Forkhead protein; Gene expression; Humans; Medicine; Medicine & Public Health; Neoplasm Recurrence, Local - drug therapy; Oncology; Original Laboratory Investigation; Proteasome inhibitors; Proteasomes; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-023-06878-3

Purpose Few targeted treatment options currently exist for patients with advanced, often recurrent breast cancers, both triple-negative breast cancer (TNBC) and hormone receptor-positive breast cancer. Forkhead box M1 (FOXM1) is an oncogenic transcription factor that drives all cancer hallmarks in all subtypes of breast cancer. We previously developed small-molecule inhibitors of FOXM1 and to further exploit their potential as anti-proliferative agents, we investigated combining FOXM1 inhibitors with drugs currently used in the treatment of breast and other cancers and assessed the potential for enhanced inhibition of breast cancer. Methods FOXM1 inhibitors alone and in combination with other cancer therapy drugs were assessed for their effects on suppression of cell viability and cell cycle progression, induction of apoptosis and caspase 3/7 activity, and changes in related gene expressions. Synergistic, additive, or antagonistic interactions were evaluated using ZIP (zero interaction potency) synergy scores and the Chou–Talalay interaction combination index. Results The FOXM1 inhibitors displayed synergistic inhibition of proliferation, enhanced G2/M cell cycle arrest, and increased apoptosis and caspase 3/7 activity and associated changes in gene expression when combined with several drugs across different pharmacological classes. We found especially strong enhanced effectiveness of FOXM1 inhibitors in combination with drugs in the proteasome inhibitor class for ER-positive and TNBC cells and with CDK4/6 inhibitors (Palbociclib, Abemaciclib, and Ribociclib) in ER-positive cells. Conclusion The findings suggest that the combination of FOXM1 inhibitors with several other drugs might enable dose reduction in both agents and provide enhanced efficacy in treatment of breast cancer.