Dual inhibition of MEK1/2 and MEK5 suppresses the EMT/migration axis in triple‐negative breast cancer through FRA‐1 regulation

Abstract

Triple‐negative breast cancer (TNBC) presents a clinical challenge due to the aggressive nature of the disease and a lack of targeted therapies. Constitutive activation of the mitogen‐activated protein kinase (MAPK)/extracellular signal‐regulated kinase (ERK) pathway has been linked to chemoresistance and metastatic progression through distinct mechanisms, including activation of epithelial‐to‐mesenchymal transition (EMT) when cells adopt a motile and invasive phenotype through loss of epithelial markers (CDH1), and acquisition of mesenchymal markers (VIM, CDH2). Although MAPK/ERK1/2 kinase inhibitors (MEKi) are useful antitumor agents in a clinical setting, including the Food and Drug Administration (FDA)‐approved MEK1,2 dual inhibitors cobimetinib and trametinib, there are limitations to their clinical utility, primarily adaptation of the BRAF pathway and ocular toxicities. The MEK5 (HGNC: MAP2K5) pathway has important roles in metastatic progression of various cancer types, including those of the prostate, colon, bone and breast, and elevated levels of ERK5 expression in breast carcinomas are linked to a worse prognoses in TNBC patients. The purpose of this study is to explore MEK5 regulation of the EMT axis and to evaluate a novel pan‐MEK inhibitor on clinically aggressive TNBC cells. Our results show a distinction between the MEK1/2 and MEK5 cascades in maintenance of the mesenchymal phenotype, suggesting that the MEK5 pathway may be necessary and sufficient in EMT regulation while MEK1/2 signaling further sustains the mesenchymal state of TNBC cells. Furthermore, additive effects on MET induction are evident through the inhibition of both MEK1/2 and MEK5. Taken together, these data demonstrate the need for a better understanding of the individual roles of MEK1/2 and MEK5 signaling in breast cancer and provide a rationale for the combined targeting of these pathways to circumvent compensatory signaling and subsequent therapeutic resistance.

The MEK5/ERK5 Pathway in Health and Disease

“…In triple negative breast cancer (TNBC) cells, Hoang et al showed that the inhibition of MEK1/2 and MEK5 using a pan-MEKi drastically decreased the migration potential of the cells compared to MEK1/2 or MEK5 inhibition alone. Even though the authors failed to show the comparative differences in vivo, the employed pan-MEKi SC-151 was effective in reducing cell viability, cellular migration, and invasion in a sub-group of aggressive TNBC cell lines [ 127 ].…”

The Unholy Trinity- Cancer cell plasticity, drug resistance and therapeutic opportunities

“…One such targeted therapy involved a combinational therapy of RAF/MEK inhibitor CH5126766 alongside Eribulin in TNBC and it was observed that this combinational mechanism was successful in inhibiting apoptosis and cell migration, thus contributing to tumor growth 68 . In another study, dual inhibition of MEK1/2 and MEK 5 by using inhibitors Cobimetinib and Trametinib resulted in the suppression of EMT in triple negative breast cancer 69 . Mohan et al have also shown that Brucein D (BD) which is an inhibitor targeting the p38 pathway lead to apoptosis and decrease viability of the breast cancer cells induced by the MAPK pathway 70 .…”

Unraveling the dangerous duet between cancer cell plasticity and drug resistance

“…One such targeted therapy involved a combinational therapy of RAF/MEK inhibitor CH5126766 with eribulin in TNBC that successfully in inhibiting apoptosis and cell migration, thus contributing to tumor growth [89]. In another study, dual inhibition of MEK1/2 and MEK 5 using inhibitors cobimetinib and trametinib resulted in the suppression of EMT in TNBC [90]. Mohan et al.…”

“…One such targeted therapy involved a combinational therapy of RAF/MEK inhibitor CH5126766 with eribulin in TNBC that successfully in inhibiting apoptosis and cell migration, thus contributing to tumor growth [89]. In another study, dual inhibition of MEK1/2 and MEK 5 using inhibitors cobimetinib and trametinib resulted in the suppression of EMT in TNBC [90]. Mohan et al have also shown that brucein D, which is an inhibitor targeting the p38 pathway leads to apoptosis and decreases the viability of breast cancer cells by inhibiting the MAPK pathway [91].…”