Targeting ERK beyond the boundaries of the kinase active site in melanoma

Abstract

Extracellular signal‐regulated kinase 1/2 (ERK1/2) constitute a point of convergence for complex signaling events that regulate essential cellular processes, including proliferation and survival. As such, dysregulation of the ERK signaling pathway is prevalent in many cancers. In the case of BRAF‐V600E mutant melanoma, ERK inhibition has emerged as a viable clinical approach to abrogate signaling through the ERK pathway, even in cases where MEK and Raf inhibitor treatments fail to induce tumor regression due to resistance mechanisms. Several ERK inhibitors that target the active site of ERK have reached clinical trials, however, many critical ERK interactions occur at other potentially druggable sites on the protein. Here we discuss the role of ERK signaling in cell fate, in driving melanoma, and in resistance mechanisms to current BRAF‐V600E melanoma treatments. We explore targeting ERK via a distinct site of protein‐protein interaction, known as the D‐recruitment site (DRS), as an alternative or supplementary mode of ERK pathway inhibition in BRAF‐V600E melanoma. Targeting the DRS with inhibitors in melanoma has the potential to not only disrupt the catalytic apparatus of ERK but also its noncatalytic functions, which have significant impacts on spatiotemporal signaling dynamics and cell fate.

GZ17-6.02 Interacts With [MEK1/2 and B-RAF Inhibitors] to Kill Melanoma Cells

“…vemurafenib, dabrafenib, encorafenib (5,6). Subsequently, it was discovered that the use of the specific mutant B-RAF inhibitors caused activation of RAF-1 and reactivation of the ERK1/2 pathway (7,8). Hence, the therapeutic modality of combined mutant B-RAF inhibition with MEK1/2 inhibition was developed, e.g.…”

Tubeimoside I Inhibits Cell Proliferation and Induces a Partly Disrupted and Cytoprotective Autophagy Through Rapidly Hyperactivation of MEK1/2-ERK1/2 Cascade via Promoting PTP1B in Melanoma

“…However, in some situations, MEK1/2-ERK1/2 plays a dual role in cell survival. ERK signaling can alter cell fates by either excessive inhibition or hyperactivation ( Sammons et al, 2019 ), even in RAS/RAF-mutant melanoma cells ( Leung et al, 2019 ).…”

Discovery of Novel Dual Extracellular Regulated Protein Kinases (ERK) and Phosphoinositide 3-Kinase (PI3K) Inhibitors as a Promising Strategy for Cancer Therapy

“…Now several drugs targeting this pathway have been approved by the FDA, such as BRAF inhibitors (Vemurafenib and Dabrafenib [4,5]) and MEK inhibitors (Trametinib, Cobimetinib and Selumetinib [6,7]). Despite the considerable success of BRAF and MEK inhibitors, with clinical studies carried out, most patients experience recurrence in less than a year and about 10~15% of patients harboring B-RafV600E are insensitive to BRAF and MEK inhibitors due to the amplification and mutation of BRAF/MEK and the negative feedback loops [8], resulting in the limiting of further clinical application. In such cases, targeting ERK, a downstream key node of BRAF/MEK, has been proposed as a potential strategy for overcoming acquired drug resistance.…”