CK2 targeting potentiates antineoplastic effects of dual HER2/EGFR inhibitor lapatinib and attenuates growth factor-induced epithelial-mesenchymal transition.
5 affiliations
- 1College of Pharmacy, Xavier University of Louisiana, 1 Drexel Dr, New Orleans, LA, 70125, USA.
- 2College of Arts and Sciences, Xavier University of Louisiana, 1 Drexel Dr, New Orleans, LA, 70125, USA.
- 3Department of Surgery and Cancer, Imperial College of London, South Kensington Campus, London, SW7 2AZ, UK.
- 4Department of Medicine, Hematology, and Medical Oncology, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA, 70112, USA.
- 5College of Pharmacy, Xavier University of Louisiana, 1 Drexel Dr, New Orleans, LA, 70125, USA. [email protected].
Abstract
Background
CK2 is a pleiotropic, heterotetrameric kinase elevated in numerous cancers and, as such, has garnered much attention as a target for novel antineoplastic agents. Currently, silmitasertib, a selective CK2 inhibitor, has an orphan designation for medulloblastoma and neuroblastoma. Tissue-specific overexpression of the catalytic subunit, CK2α, is sufficient to drive the development of mammary tumors in mice, underlying its potential role in breast oncogenesis. Our lab has demonstrated that CK2β protein expression is associated with endocrine resistance and that targeted disruption of CK2 activity results in ERα proteolysis. Among the factors driving endocrine resistance is overexpression of HER2/EGFR, which contributes to both proliferation and phenotypic plasticity in ER⁺ breast cancer. Here, we sought to determine the impact of CK2 targeting on HER2/EGFR signaling, phenotypic plasticity, and cell proliferation in endocrine-sensitive and endocrine-resistant breast cancer. Furthermore, we explored the potential of combined lapatinib and CK2-based therapies in decreasing breast cancer proliferation and epithelial-mesenchymal transition (EMT).Methods
CK2 subunit expression and function were investigated in ERα-mutant, tamoxifen-resistant MCF-7 Y537S breast cancer cells and additional breast cancer subtypes. CK2 was inhibited pharmacologically using CX-4945 or genetically via shRNA knockdown of CK2β. Cell proliferation, spheroid growth, migration, and EMT markers were assessed using live-cell imaging, wound-healing assays, immunoblotting, and qRT-PCR. Publicly available patient datasets were analyzed to evaluate the prognostic relevance of CSNK2B expression.Results
CK2β expression was significantly upregulated in ERα-mutant breast cancer cells and patient tumors. Pharmacological inhibition or genetic depletion of CK2β suppressed proliferation, spheroid formation, and migration, accompanied by reduced ERK phosphorylation and cyclin D1 expression. CK2β inhibition also attenuated EMT, marked by decreased N-cadherin, vimentin, and EMT transcription factors, while enhancing E-cadherin expression. High CSNK2B expression correlated with poorer relapse-free survival, particularly in ERα⁺ and HER2-E breast cancers. Notably, CK2β inhibition sensitized breast cancer cells to HER2-targeted therapy.Conclusions
CK2 is a critical regulator of endocrine-resistant breast cancer progression, promoting proliferation, EMT, and therapeutic resistance through ERK/cyclin D1 signaling. Inhibition of CK2 potentiated the effects of lapatinib across several cell lines. Furthermore, shRNA-mediated knockdown of the CK2β subunit phenocopies pharmacological disruption of CK2 and highlights the significance of the regulatory subunit in breast cancer cell biology. Targeting CK2, and, more selectively, CK2β represent a promising approach to overcome endocrine resistance and enhance responsiveness to HER2-directed treatments.
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BibTeX
@article{robinson2026targeting,
title = {{CK2 targeting potentiates antineoplastic effects of dual HER2/EGFR inhibitor lapatinib and attenuates growth factor-induced epithelial-mesenchymal transition.}},
author = {DeZha Robinson and Hogyoung Kim and Alexandra Selico-Dunn and Emma Elkins and Sichan Kim and Sihyoung Kim and Clark Perkins and Emily Schenk-Smith and Simak Ali and Matthew Burow and Christopher Williams},
journal = {Breast cancer research : BCR},
year = {2026},
month = aug,
doi = {10.1186/s13058-026-02356-y},
url = {https://europepmc.org/article/MED/42958296},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - CK2 targeting potentiates antineoplastic effects of dual HER2/EGFR inhibitor lapatinib and attenuates growth factor-induced epithelial-mesenchymal transition.
AU - DeZha Robinson
AU - Hogyoung Kim
AU - Alexandra Selico-Dunn
AU - Emma Elkins
AU - Sichan Kim
AU - Sihyoung Kim
AU - Clark Perkins
AU - Emily Schenk-Smith
AU - Simak Ali
AU - Matthew Burow
AU - Christopher Williams
PY - 2026
DA - 2026/08/02
JO - Breast cancer research : BCR
DO - 10.1186/s13058-026-02356-y
UR - https://europepmc.org/article/MED/42958296
AB - Background CK2 is a pleiotropic, heterotetrameric kinase elevated in numerous cancers and, as such, has garnered much attention as a target for novel antineoplastic agents. Currently, silmitasertib, a selective CK2 inhibitor, has an orphan designation for medulloblastoma and neuroblastoma. Tissue-specific overexpression of the catalytic subunit, CK2α, is sufficient to drive the development of mammary tumors in mice, underlying its potential role in breast oncogenesis. Our lab has demonstrated that CK2β protein expression is associated with endocrine resistance and that targeted disruption of CK2 activity results in ERα proteolysis. Among the factors driving endocrine resistance is overexpression of HER2/EGFR, which contributes to both proliferation and phenotypic plasticity in ER⁺ breast cancer. Here, we sought to determine the impact of CK2 targeting on HER2/EGFR signaling, phenotypic plasticity, and cell proliferation in endocrine-sensitive and endocrine-resistant breast cancer. Furthermore, we explored the potential of combined lapatinib and CK2-based therapies in decreasing breast cancer proliferation and epithelial-mesenchymal transition (EMT).Methods CK2 subunit expression and function were investigated in ERα-mutant, tamoxifen-resistant MCF-7 Y537S breast cancer cells and additional breast cancer subtypes. CK2 was inhibited pharmacologically using CX-4945 or genetically via shRNA knockdown of CK2β. Cell proliferation, spheroid growth, migration, and EMT markers were assessed using live-cell imaging, wound-healing assays, immunoblotting, and qRT-PCR. Publicly available patient datasets were analyzed to evaluate the prognostic relevance of CSNK2B expression.Results CK2β expression was significantly upregulated in ERα-mutant breast cancer cells and patient tumors. Pharmacological inhibition or genetic depletion of CK2β suppressed proliferation, spheroid formation, and migration, accompanied by reduced ERK phosphorylation and cyclin D1 expression. CK2β inhibition also attenuated EMT, marked by decreased N-cadherin, vimentin, and EMT transcription factors, while enhancing E-cadherin expression. High CSNK2B expression correlated with poorer relapse-free survival, particularly in ERα⁺ and HER2-E breast cancers. Notably, CK2β inhibition sensitized breast cancer cells to HER2-targeted therapy.Conclusions CK2 is a critical regulator of endocrine-resistant breast cancer progression, promoting proliferation, EMT, and therapeutic resistance through ERK/cyclin D1 signaling. Inhibition of CK2 potentiated the effects of lapatinib across several cell lines. Furthermore, shRNA-mediated knockdown of the CK2β subunit phenocopies pharmacological disruption of CK2 and highlights the significance of the regulatory subunit in breast cancer cell biology. Targeting CK2, and, more selectively, CK2β represent a promising approach to overcome endocrine resistance and enhance responsiveness to HER2-directed treatments.
SN - 1465-5411
SN - 1465-542X
ER -