Inhibiting ERK5 Overcomes Breast Cancer Resistance to Anti-HER2 Therapy By Targeting the G1–S Cell-Cycle Transition

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

Research output: Contribution to journalArticlepeer-review

Abstract

Targeting HER2 has become 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 antiHER2 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 antiproliferative activity of single-agent anti-HER2 therapy in resistant breast cancer cell lines by causing a G 1 cell-cycle arrest. Moreover, ERK5 knockdown restored the antitumor 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. Significance: Here we demonstrate that targeting ERK5 in HER2-positive breast cancer cells reduces the level of phosphorylation of RB, an important mediator of the G 1–S transition. This effect is associated with increased antitumor activity of lapatinib in combination therapy with ERK5 silencing. Collectively, these findings reveal that ERK5 constitutes a relevant therapeutic target for the many patients with resistant HER2-positive breast cancer.

Original languageEnglish
Pages (from-to)131-145
Number of pages15
JournalCancer Research Communications
Volume2
Issue number3
DOIs
Publication statusPublished - 10 Mar 2022

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