Mechanisms and strategies to overcome resistance to molecularly targeted therapy for melanoma

Su Yin Lim, Alexander M. Menzies, Helen Rizos*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

90 Citations (Scopus)


The identification of driver mutations in melanoma has changed the field of cancer treatment. BRAF and NRAS mutations are predominant in melanoma and lead to overactivation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways. Selective inhibitors targeting key effectors of the MAPK pathway have revolutionized the treatment of patients with advanced metastatic BRAF-mutant melanoma. However, resistance to therapy is almost universal and remains a major challenge in clinical care, with the majority of patients progressing within 1 year. Dissecting the mechanisms of resistance to targeted therapies may offer new insights into strategies for overcoming resistance. This review describes the efficacy of therapies targeting the MAPK and PI3K/AKT signaling pathways in melanoma, details the mechanisms contributing to drug resistance, and discusses current approaches to improving outcomes further.

Original languageEnglish
Pages (from-to)2118-2129
Number of pages12
Publication statusPublished - 1 Jun 2017


  • BRAF inhibitors
  • immunotherapy
  • melanoma
  • mitogen-activated protein kinase (MAPK) pathway
  • mitogen-activated protein kinase kinase (MEK) inhibitors
  • phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway
  • targeted therapy


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