TY - JOUR
T1 - Effective combination treatments for breast cancer inhibition by FOXM1 inhibitors with other targeted cancer drugs
AU - Guillen, Valeria Sanabria
AU - Ziegler, Yvonne
AU - Gopinath, Chirag
AU - Kumar, Sandeep
AU - Dey, Parama
AU - Plotner, Blake N.
AU - Dawson, Nadia Z.
AU - Kim, Sung Hoon
AU - Katzenellenbogen, John A.
AU - Katzenellenbogen, Benita S.
N1 - Funding Information:
This research was supported by grants from the Breast Cancer Research Foundation (BCRF-083 to BSK and BCRF-084 to JAK and BSK) and the NIH/NCI (1R01 CA220284 to BSK and JAK), the Julius and Mary Landfield Cancer Research Fund (to BSK), and the NIH Training Program T32 GMO70421 Fellowship to VSG.
Funding Information:
This research was supported by grants from the Breast Cancer Research Foundation (BCRF-083 to BSK and BCRF-084 to JAK and BSK), the NIH/NCI (1R01 CA220284 to BSK and JAK), the Julius and Mary Landfield Cancer Research Fund (to BSK), and the NIH Training Program T32 GMO70421 Fellowship to VSG.
Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2023/4
Y1 - 2023/4
N2 - 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.
AB - 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.
KW - Breast cancer suppression
KW - CDK4/6
KW - FOXM1 inhibitors
KW - Inhibitors
KW - Proteasome inhibitors
KW - Synergy
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U2 - 10.1007/s10549-023-06878-3
DO - 10.1007/s10549-023-06878-3
M3 - Article
C2 - 36847915
AN - SCOPUS:85149015196
SN - 0167-6806
VL - 198
SP - 607
EP - 621
JO - Breast Cancer Research and Treatment
JF - Breast Cancer Research and Treatment
IS - 3
ER -