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



Zhang, Jingwei, Pearson, Adam J, Sabherwal, Nitin, Telfer, Brian A, Ali, Nisha, Kan, Karmern, Xu, Qiuping, Zhang, Wei, Chen, Fuhui, Li, Shiyang
et al (show 8 more authors) (2022) Inhibiting ERK5 Overcomes Breast Cancer Resistance to Anti-HER2 Therapy By Targeting the G1–S Cell-Cycle Transition. Cancer Research Communications, 2 (3). pp. 131-145.

Access the full-text of this item by clicking on the Open Access link.

Abstract

<jats:p>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 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 antiproliferative 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 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.</jats:p> <jats:sec> <jats:title>Significance:</jats:title> <jats:p>Here we demonstrate that targeting ERK5 in HER2-positive breast cancer cells reduces the level of phosphorylation of RB, an important mediator of the G1–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.</jats:p> </jats:sec>

Item Type: Article
Uncontrolled Keywords: Humans, Breast Neoplasms, Quinazolines, Protein Kinases, Antineoplastic Agents, Cell Cycle, Female
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 14 Nov 2022 09:38
Last Modified: 06 Aug 2023 00:59
DOI: 10.1158/2767-9764.crc-21-0089
Open Access URL: https://doi.org/10.1158/2767-9764.CRC-21-0089
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3166184