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Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
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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
PubMed

Insights

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.
Keywords:
ASN007BVD523 (Ulixertinib)GDC0994 (Ravoxertinib)MAP kinaseMEKSCH772984Temuterkib (LY3214996)cisplatinerkp38

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