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  3. Exploiting metabolic adaptations to overcome dabrafenib treatment resistance in melanoma cells

Exploiting metabolic adaptations to overcome dabrafenib treatment resistance in melanoma cells

  • Mol Oncol. 2025 Dec 2. doi: 10.1002/1878-0261.70169.
Silvia Eller 1,  Susanne Ebner 1,  Carmen Haselrieder 1,  Julia K Günther 1,  Astrid Drasche 1,  Sophie Strich 2 3,  Chiara Volani 4,  Andrea Medici 1,  Aleksandar Nikolajevic 1,  Alex Deltedesco 1,  Johannes E Sigmund 1,  Michael J Blumer 5,  Martin Hermann 6,  Johanna Vanacker 1,  Gerald Brandacher 1,  Eduard Stefan 2 3,  Omar Torres-Quesada 3 7,  Jakob Troppmair 1
Affiliations

Affiliations

  • 1 Daniel Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Austria.
  • 2 Institute of Molecular Biology and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Austria.
  • 3 Tyrolean Cancer Research Institute (TKFI), Innsbruck, Austria.
  • 4 Deparment of Internal Medicine II, Medical University of Innsbruck, Austria.
  • 5 Department of Anatomy, Histology and Embryology, Institute of Clinical and Functional Anatomy, Medical University of Innsbruck, Austria.
  • 6 Department of Anaesthesia and Intensive Care Medicine, Medical University of Innsbruck, Austria.
  • 7 Division of Medical Biochemistry, Biocenter, Medical University of Innsbruck, Austria.
PMID: 41332139 DOI: 10.1002/1878-0261.70169
Abstract

The emergence of resistance to mutant BRAF-specific inhibitors (BRAFi) requires novel strategies for melanoma treatment. The progression of these tumors involves metabolic adaptations, which also affect the cellular redox status. Previous studies have linked Raf kinase signaling, a key component of the MAPK/ERK pathway involved in cell division and survival, to the suppression of mitochondrial Reactive Oxygen Species (ROS) production, resulting in protection against cell death. In BRAF-transformed cells, we have identified impaired JNK1/2-dependent activation of the mitochondrial prooxidant protein p66Shc as a potential cause. In the present study, we dissected signaling and mitochondrial alterations that characterize the transition from BRAFi responsiveness to resistance in A375 melanoma cells. Insensitivity to BRAFi dabrafenib exposure was associated with reactivation of ERK1/2 phosphorylation, increased JNK1/2 kinase activity, p66ShcS36 phosphorylation, and elevated ROS production. Utilizing high-resolution respirometry (HRR) and transmission electron microscopy (TEM), we show that dabrafenib-resistant cells displayed mitochondrial damage, compensated by increased respiration, leading to high ROS levels. Moreover, dabrafenib-resistant cells (A375D) have more efficient antioxidant systems, which may explain why despite ongoing cell death, net cell growth was observed. Treatment of both parental and resistant cells with phenethyl isothiocyanate (PEITC) increased ROS production but caused substantial cell death only in A375D melanoma cells. This PEITC effect could be demonstrated in two further dabrafenib-resistant cell lines, WM164D and 451LuP. These results suggest that the altered redox status is linked to compromised mitochondria and is associated with the development of BRAFi resistance, rendering cells exquisitely sensitive to the actions of selective ROS-inducing therapeutics.

Keywords

BRAFV600E; dabrafenib resistance; high‐resolution respirometry; melanoma; mitochondria; p66Shc.

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