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Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants
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A critical role of FAK signaling in Rac1-driven melanoma cell resistance to MAPK pathway inhibition

Jesse D Riordan1,2, Teagan A Nathanson2,3, Afshin Varzavand2,3

  • 1Department of Anatomy & Cell Biology, The University of Iowa, Iowa City, IA, USA.

Oncogene
|October 18, 2025
PubMed

Insights

Rac1 mutations drive melanoma resistance to targeted therapies by activating multiple signaling pathways. Combining BRAF/MEK inhibitors with FAK inhibitors shows promise for treating this aggressive form of skin cancer.

Area of Science:

  • Oncology
  • Dermatology
  • Molecular Biology

Background:

  • The Rac1 P29S mutation in cutaneous melanoma confers resistance to MAPK pathway inhibitors (MAPKi) and is linked to poor clinical outcomes.
  • Activation of Rac1 guanine exchange factors (GEFs) exacerbates MAPKi resistance, especially in undifferentiated melanoma cells.

Purpose of the Study:

  • To elucidate the mechanisms underlying Rac1-driven MAPKi resistance in melanoma.
  • To identify therapeutic strategies to overcome Rac1-mediated resistance and inhibit tumor growth.

Main Methods:

  • Analysis of resistance mechanisms in Rac1-driven melanoma models.
  • Investigating the role of alternative MAPK pathways (Jun kinase, p38) and YAP/TAZ signaling.
  • Assessing the dependency on focal adhesion kinase (FAK) signaling.
  • Evaluating the efficacy of combined RAF/MEK inhibition (avutometinib) and FAK inhibition (defactinib).

Main Results:

  • Rac1-driven melanomas exhibit multifaceted resistance, including reduced BRAF/MEK dependence, activation of Jun kinase and p38 pathways, and partial YAP/TAZ signaling reliance.
  • Despite reduced BRAF/MEK dependence, melanoma cells remain partially ERK-dependent.
  • Activated Rac1 induces a dependency on FAK signaling in undifferentiated melanoma cells.

Conclusions:

  • Combined inhibition of RAF/MEK with avutometinib and FAK with defactinib effectively suppresses growth in Rac1-driven melanoma cells.
  • This combination therapy holds promise for treating heavily pre-treated, advanced cutaneous melanoma with Rac1-driven MAPKi resistance, including brain metastases.

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