Inhibiting ERK5 overcomes breast cancer resistance to anti-HER2 therapy by targeting the G1/S cell cycle transition.

Abstract

Targeting the human epidermal growth factor receptor 2 (HER2) became a landmark in the treatment of HER2-driven breast cancer. Nonetheless, the clinical efficacy of anti-HER2 therapies can be short-lived and a significant proportion of patients ultimately develop metastatic disease and die. One striking consequence of oncogenic activation of HER2 in breast cancer cells is the constitutive activation of the extracellular-regulated protein kinase 5 (ERK5) through its hyperphosphorylation. In this study, we sought to decipher the significance of this unique molecular signature in promoting therapeutic resistance to anti-HER2 agents. We found that a small-molecule inhibitor of ERK5 suppressed the phosphorylation of the retinoblastoma protein (RB) in HER2 positive breast cancer cells. As a result, ERK5 inhibition enhanced the anti-proliferative activity of single-agent anti-HER2 therapy in resistant breast cancer cell lines by causing a G1 cell cycle arrest. Moreover, ERK5 knockdown restored the anti-tumor activity of the anti-HER2 agent lapatinib in human breast cancer xenografts. Taken together, these findings support the therapeutic potential of ERK5 inhibitors to improve the clinical benefit that patients receive from targeted HER2 therapies.

• Authors: Jingwei Zhang, Adam J Pearson, Nitin Sabherwal, Brian A Telfer, Nisha Ali, Karmern Kan, Qiuping Xu, Wei Zhang, Fuhui Chen, Shiyang Li, Jinhua Wang, Nathanael S Gray, Blanca Risa-Ebrí, Katherine G Finegan, Michael J Cross, Emanuele Giurisato, Alan J Whitmarsh, Cathy Tournier
• Journal: Cancer research communications (Cancer Res Commun) Vol. 2 Issue 3 Pg. 131-145 (03 10 2022) ISSN: 2767-9764 [Electronic] United States
• PMID: 36466034 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Protein Kinases
• Quinazolines

Topics

• Humans
• Female
• Breast Neoplasms (drug therapy)
• Antineoplastic Agents (pharmacology)
• Protein Kinases (therapeutic use)
• Quinazolines (pharmacology)
• Cell Cycle