Erk inhibitors intercept Erk-mediated negative feedback while imposing cell-cycle arrest and activating p38
Merav Darash-Yahana1, Nadine Soudah1, Alexey Baskin1
1Department of Biological Chemistry, The Institute of Life Science, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Iscience
|July 13, 2026
Summary
Mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitors targeting Erk1/2 show promise in cancer therapy. However, these inhibitors can paradoxically reactivate oncogenic pathways, necessitating combination treatments to prevent disease recurrence.
Area of Science:
- Oncology
- Molecular Biology
- Signal Transduction
Background:
- Mitogen-activated protein kinases (MAPKs), specifically Erk1/2, are crucial in the receptor tyrosine kinase (RTK)-Ras-Raf-MEK signaling pathway.
- Aberrant activation of this pathway is common in various cancers, positioning Erk1/2 as a therapeutic target.
- Erk1/2 signaling promotes cell proliferation but also exerts negative feedback on upstream components, potentially leading to pathway reactivation and resistance.
Purpose of the Study:
- To investigate the effects of various Erk1/2 inhibitors on cancer cell lines, including those with specific Erk1 mutations.
- To assess the impact of these inhibitors on cell cycle progression, upstream signaling, and phosphoproteome.
- To determine the potential for pathway reactivation and identify strategies to overcome resistance.
Main Methods:
- Treatment of cancer cell lines with Erk1/2 inhibitors (BVD523, GDC0994, SCH772984, ASN007, Temuterkib).
- Analysis of Erk1/2 phosphorylation to confirm pathway inhibition.
- Cell cycle analysis (G1 arrest).
- Assessment of p38 activation.
- Phosphoproteomic profiling following BVD523 treatment.
Main Results:
- All tested inhibitors effectively phosphorylated Erk1/2, indicating inhibition of negative feedback.
- A consistent G1 cell cycle arrest and p38 activation were observed across all treatments.
- Partial cell viability was maintained even after prolonged treatment (72 hours).
- BVD523 induced significant alterations in the phosphoproteome.
- Evidence of pathway reactivation was suggested by sustained Erk phosphorylation.
Conclusions:
- Erk1/2 inhibitors are effective in blocking the oncogenic RTK-Ras-Raf-MEK cascade and inducing cell cycle arrest.
- The observed negative feedback inhibition and partial cell viability highlight the potential for resistance.
- Combination therapies involving Erk1/2 inhibitors and agents preventing pathway reactivation are crucial for sustained therapeutic efficacy in cancer treatment.
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