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Acyclic Retinoid Attenuates STAT3 Signaling and Reduces In Vitro Growth of A375-Derived Dabrafenib Plus

Mitsuaki Nishizawa1, Masanori Kimura1, Hinata Hamada1

  • 1Department of Bioscience and Engineering, College of Systems Engineering and Science, Shibaura Institute of Technology, Fukasaku 307, Minuma-ku, Saitama 337-8570, Japan.

International Journal of Molecular Sciences
|July 28, 2026
PubMed

Insights

Acyclic retinoid (ACR) shows promise in overcoming resistance to BRAF and MEK inhibitors in melanoma. ACR reduced cell viability and growth in resistant melanoma cells, suggesting potential as a non-MAPK adjunct therapy.

Area of Science:

  • Oncology
  • Dermatology
  • Molecular Biology

Background:

  • BRAF-mutant melanoma often develops resistance to combined BRAF and MEK inhibitors, limiting durable disease control.
  • Acyclic retinoid (ACR; peretinoin) is a clinically studied retinoid with incompletely defined activity in MAPK inhibitor-resistant melanoma.

Purpose of the Study:

  • To establish and characterize melanoma cell models resistant to combined BRAF and MEK inhibition.
  • To evaluate the in vitro efficacy of Acyclic Retinoid (ACR) in a BRAF and MEK inhibitor-resistant melanoma model.

Main Methods:

  • Established dabrafenib plus trametinib-resistant melanoma clones (A375P-derived).
  • Evaluated ACR's effect on viability, clonogenic growth, and molecular markers (STAT3, EGFR, Cyclins, p27KIP1) in resistant A375PDTR-D cells.
  • Assessed ACR's impact on MAPK pathway phosphorylation (ERK, JNK) and AKT phosphorylation.

Main Results:

  • Resistant clones maintained viability and ERK phosphorylation under combined inhibition.
  • ACR reduced short-term viability and clonogenic growth in A375PDTR-D cells.
  • ACR decreased STAT3 Tyr705 phosphorylation, EGFR, Cyclin D1, Cyclin B1 expression, and increased p27KIP1, without affecting AKT or MEK/ERK phosphorylation.

Conclusions:

  • ACR demonstrates potential as a non-MAPK adjunct strategy for BRAF and MEK inhibitor-resistant melanoma.
  • Further studies are needed to establish generalizability, drug interactions, direct cellular effects, and in vivo efficacy.
Keywords:
Cyclin D1EGFRSTAT3acyclic retinoiddabrafenibdrug resistancemelanomap27KIP1peretinointrametinib

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