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Review Open Access

Targeted therapy in BRAF‑mutant melanoma: Advances and challenges (Review)

  • Authors:
    • Lu Zhang
    • Dongliang Shen
    • Jianguo Feng
    • Liling Tang
  • View Affiliations / Copyright

    Affiliations: Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, P.R. China, Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
    Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 88
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    Published online on: June 4, 2026
       https://doi.org/10.3892/ijo.2026.5901
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Abstract

Over half of patients with melanoma exhibit v‑Raf murine sarcoma viral oncogene homolog B (BRAF) mutations, which drive hyperactivation of the MAPK pathway and confer high proliferative potential. To target this oncogenic mutation, BRAF inhibitors, as well as MEK inhibitors (targeting the downstream effector of BRAF), have been approved for melanoma therapy. Although these inhibitors initially decrease the tumor burden, nearly all patients eventually develop drug resistance, leading to aggressive disease relapse at both the primary and metastatic sites. Understanding the mechanisms underlying tumor escape from drug lethality is crucial for the development of strategies against melanoma. The present study aimed to summarize the discovery, development and clinical evolution of the BRAF and MEK inhibitors approved for the treatment of melanoma, their notable efficacy in suppressing aggressive melanoma progression and the underlying mechanisms of acquired resistance.
View Figures

Figure 1

Timeline of clinical trials and US
Food and Drug Administration approval for BRAF and MEK inhibitors
in melanoma therapy. Dates indicate the study start dates. All data
were sourced from ClinicalTrials.gov (clinicaltrials.gov).

Figure 2

Acquisition of drug resistance in
melanoma. Melanoma is highly heterogenous and exhibits phenotypic
plasticity, enabling phenotypic switching in response to MAPKi
treatment. In the early-treatment phase, MAPKi-mediated induction
of cell death preferentially targets MITF-high melanoma
populations, leading to tumor shrinkage within a short timeframe.
Cells expressing high levels of RTKs, such as AXL receptor tyrosine
kinase and nerve growth factor receptor, are intrinsically
resistant to MAPKi and survive drug-induced cell death. The
duration of this drug-tolerant phase varies and dormant cells
typically suppress proliferative signals to evade immune
surveillance. Through epigenetic reprogramming, residual tumor
cells acquire an invasive phenotype, facilitating dissemination to
distant organs, or a dedifferentiated phenotype, enabling them to
evade continuous drug pressure until they develop secondary
mutations (64,71,169). i, inhibitor; MITF,
microphthalmia-associated transcription factor; RTK, receptor
tyrosine kinase.
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Copy and paste a formatted citation
Spandidos Publications style
Zhang L, Shen D, Feng J and Tang L: Targeted therapy in BRAF‑mutant melanoma: Advances and challenges (Review). Int J Oncol 69: 88, 2026.
APA
Zhang, L., Shen, D., Feng, J., & Tang, L. (2026). Targeted therapy in BRAF‑mutant melanoma: Advances and challenges (Review). International Journal of Oncology, 69, 88. https://doi.org/10.3892/ijo.2026.5901
MLA
Zhang, L., Shen, D., Feng, J., Tang, L."Targeted therapy in BRAF‑mutant melanoma: Advances and challenges (Review)". International Journal of Oncology 69.2 (2026): 88.
Chicago
Zhang, L., Shen, D., Feng, J., Tang, L."Targeted therapy in BRAF‑mutant melanoma: Advances and challenges (Review)". International Journal of Oncology 69, no. 2 (2026): 88. https://doi.org/10.3892/ijo.2026.5901
Copy and paste a formatted citation
x
Spandidos Publications style
Zhang L, Shen D, Feng J and Tang L: Targeted therapy in BRAF‑mutant melanoma: Advances and challenges (Review). Int J Oncol 69: 88, 2026.
APA
Zhang, L., Shen, D., Feng, J., & Tang, L. (2026). Targeted therapy in BRAF‑mutant melanoma: Advances and challenges (Review). International Journal of Oncology, 69, 88. https://doi.org/10.3892/ijo.2026.5901
MLA
Zhang, L., Shen, D., Feng, J., Tang, L."Targeted therapy in BRAF‑mutant melanoma: Advances and challenges (Review)". International Journal of Oncology 69.2 (2026): 88.
Chicago
Zhang, L., Shen, D., Feng, J., Tang, L."Targeted therapy in BRAF‑mutant melanoma: Advances and challenges (Review)". International Journal of Oncology 69, no. 2 (2026): 88. https://doi.org/10.3892/ijo.2026.5901
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