Melanoma is a type of skin cancer in which nearly half of patients have mutations in the BRAF gene that accelerate tumor growth. Although BRAF-targeted treatments, known as BRAF inhibitors, work well initially, tumors often find ways to fight back. Adaptive metabolic reprogramming with oxidative phosphorylation, anaerobic glycolysis, and autophagy are the main mechanisms of resistance, both de novo and acquired, to MAP-kinase (MAPKi) pathway inhibitors in melanoma. MAPKi-resistant melanoma cells activate alternative pathways such as the PI3K-cAkt pathway, which suppresses cell death, mTOR for growth factors-dependent protein synthesis, or induce the expression and activation of transcription factors such as CREB.
In new research, scientists explored how the cellular protein GSK3β becomes more active in melanoma cells that develop resistance to B-Raf inhibitors. GSK3β is a protein kinase found in all cells that regulates glycogen metabolism, gene transcription, and cell survival. Although its oncogenic role is poorly understood, early indirect evidence showed that activating GSK3β protected melanoma cells from apoptosis, while inhibiting it prevented melanoma cell growth in mice both in vivo and in vitro. Scientists also know that it is part of the Wnt-beta catenin signaling system, which is needed for both embryogenesis and for tumor cells to be aggressive and metastasize.
Researchers treated melanoma cells with a common V600E B-Raf mutation using Dabrafenib, a clinically used B-Raf inhibitor. Over time, the cancer cells developed resistance and showed a marked increase in GSK3β levels. This pattern was confirmed across multiple melanoma cell models, suggesting that the finding is consistent and reliable. Importantly, the researchers observed that treating resistant cancer cells with a GSK3β inhibitor called LY2090314 significantly reduced their growth. This result suggests that blocking this protein could restore sensitivity to treatment, highlighting GSK3β as a promising therapeutic target and supporting the idea of combining available GSK3β inhibitors with existing melanoma anticancer drugs.
The research perspective adds to ongoing efforts to understand and overcome melanoma drug resistance. It shows that resistance is not driven only by genetic mutations but may also involve adaptive changes in the intracellular signaling and survival mechanisms. By identifying GSK3β as a potential contributor, the authors offer a new direction for improving the durability of targeted treatments in melanoma. As research continues, GSK3β may be a critical factor in the long-term success of melanoma therapy, particularly for patients who have stopped responding to standard BRAF-targeted drugs.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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