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

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 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. 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 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.

A multi-omics integrative approach unravels novel genes and pathways associated with senescence escape after targeted therapy in NRAS mutant melanoma

“…Interestingly, all those pathways have been shown to activate ERK5. In breast cancer, ERK5 contributes to the response to EGF stimulation [ 55 ] and is involved in the resistance to ErbB-2 (HER2) inhibitors by facilitating G1-S transition [ 56 ]. In BRAF mutant melanoma resistant to BRAFi and MEKi, IGF1R activation induces ERK5 phosphorylation [ 57 ].…”

BAY-885, a mitogen-activated protein kinase kinase 5 inhibitor, induces apoptosis by regulating the endoplasmic reticulum stress/Mcl-1/Bim pathway in breast cancer cells

“…The MEK5/ERK5 axis represses estrogen receptor expression and promotes hormone-independent tumorigenesis in BC [ 14 ]. A recent study showed that inhibition of ERK5 enhanced the efficacy of anti-HER2 agent lapatinib in human breast cancer xenografts [ 15 ]. Thus, targeting the MEK5/ERK5 axis might be a potential strategy for the treatment of BC.…”

Modulation of ERK5 Activity as a Therapeutic Anti-Cancer Strategy

“…29 There are also reports of ERK5 perturbation with shRNA stimulating the growth of breast cancer xenografts. 30,31 Clearly, while there is experimental evidence linking ERK5 to tumor cell proliferation in some cell models, it is not a universal phenomenon. ERK5 gene knockout studies in mice have shown it to have an indispensable role in angiogenesis and heart development, with ERK5 loss resulting in cardiac defects and embryonic lethality.…”

“…Despite these observations, the proliferation of many tumor cells is not impacted by the genetic perturbation of ERK5, including cells where ERK5 is overexpressed or MAPK7 is amplified . There are also reports of ERK5 perturbation with shRNA stimulating the growth of breast cancer xenografts. , Clearly, while there is experimental evidence linking ERK5 to tumor cell proliferation in some cell models, it is not a universal phenomenon.…”

“… 29 There are also reports of ERK5 perturbation with shRNA stimulating the growth of breast cancer xenografts. 30 , 31 Clearly, while there is experimental evidence linking ERK5 to tumor cell proliferation in some cell models, it is not a universal phenomenon.…”