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CARM1-Mediated MAP2K4 Methylation Potentiates the Oncogenic Functions of MAP2K4 and Constitutes a Targetable

Eui-Jun Kim1,2, Yidan Wang1,2, Yu-Lin Chen1,2

  • 1McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin.

Cancer Research
|May 29, 2025
PubMed

Insights

Coactivator-associated arginine methyltransferase 1 (CARM1) inhibition in triple-negative breast cancer (TNBC) activates AKT, leading to resistance. Combining CARM1 inhibitors with PI3K inhibitors shows synergistic anticancer effects in TNBC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Coactivator-associated arginine methyltransferase 1 (CARM1) is overexpressed in triple-negative breast cancer (TNBC).
  • CARM1 inhibitors (CARM1i) are being developed, but CARM1i treatment can paradoxically increase CARM1 levels and activate AKT, potentially causing resistance.

Purpose of the Study:

  • To investigate the mechanism by which CARM1 inhibition affects signaling pathways in TNBC.
  • To identify potential combination therapies to overcome CARM1i resistance.

Main Methods:

  • Investigated CARM1 methylation of MAP2K4 in TNBC cells.
  • Assessed the effects of CARM1i on AKT and JNK signaling pathways.
  • Evaluated the efficacy of combining CARM1i with PI3K inhibitors in TNBC models.

Main Results:

  • CARM1 methylates MAP2K4 at arginine 58, promoting its nuclear localization and activation of JNK signaling, which drives proliferation and metastasis.
  • CARM1i treatment inhibits MAP2K4 methylation, leading to AKT activation via abrogating the MAP2K4-PI3K signaling feedback loop.
  • Combination therapy with CARM1i and PI3K inhibitors demonstrated synergistic anticancer effects in TNBC cell lines, organoids, and patient-derived xenografts.

Conclusions:

  • CARM1 inhibition disrupts the MAP2K4-PI3K signaling axis, offering a rationale for combination therapy.
  • Combining CARM1i with PI3K inhibitors can enhance therapeutic sensitivity in TNBC.
  • This study provides a novel therapeutic strategy to overcome resistance to CARM1 inhibitors in TNBC.

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