Effects of BRAF mutations and BRAF inhibition on immune responses to melanoma

• Published in: Molecular cancer therapeutics Vol. 13; no. 12; pp. 2769 - 2783
• Main Authors: Ilieva, Kristina M, Correa, Isabel, Josephs, Debra H, Karagiannis, Panagiotis, Egbuniwe, Isioma U, Cafferkey, Michiala J, Spicer, James F, Harries, Mark, Nestle, Frank O, Lacy, Katie E, Karagiannis, Sophia N
• Format: Journal Article
• Language: English
• Published: United States 01.12.2014
• Subjects: Animals; Combined Modality Therapy; Enzyme Activation; Humans; Melanoma - genetics; Melanoma - immunology; Melanoma - metabolism; Melanoma - therapy; Molecular Targeted Therapy; Mutation; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins B-raf - antagonists & inhibitors; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins B-raf - immunology; Signal Transduction - drug effects; Translational Research, Biomedical; Tumor Escape
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.mct-14-0290

Malignant melanoma is associated with poor clinical prognosis; however, novel molecular and immune therapies are now improving patient outcomes. Almost 50% of melanomas harbor targetable activating mutations of BRAF that promote RAS-RAF-MEK-ERK pathway activation and melanoma proliferation. Recent evidence also indicates that melanomas bearing mutant BRAF may also have altered immune responses, suggesting additional avenues for treatment of this patient group. The small molecule inhibitors selective for mutant BRAF induce significant but short-lived clinical responses in a proportion of patients, but also lead to immune stimulatory bystander events, which then subside with the emergence of resistance to inhibition. Simultaneous BRAF and MEK inhibition, and especially combination of BRAF inhibitors with new immunotherapies such as checkpoint blockade antibodies, may further enhance immune activation, or counteract immunosuppressive signals. Preclinical evaluation and ongoing clinical trials should provide novel insights into the role of immunity in the therapy of BRAF-mutant melanoma.