Effects of BRAF mutations and BRAF inhibition on immune responses to melanoma.
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.
St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine and NIHR Biomedical Research Centre at Guy's and St. Thomas's Hospitals and King's College London, London, United Kingdom.
Kristina M
KM
Ilieva
St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine and NIHR Biomedical Research Centre at Guy's and St. Thomas's Hospitals and King's College London, London, United Kingdom.
Isabel
I
Correa
St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine and NIHR Biomedical Research Centre at Guy's and St. Thomas's Hospitals and King's College London, London, United Kingdom. Department of Research Oncology, Division of Cancer Studies, King's College London, Guy's Hospital, London, United Kingdom.
Debra H
DH
Josephs
St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine and NIHR Biomedical Research Centre at Guy's and St. Thomas's Hospitals and King's College London, London, United Kingdom.
Panagiotis
P
Karagiannis
St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine and NIHR Biomedical Research Centre at Guy's and St. Thomas's Hospitals and King's College London, London, United Kingdom.
Isioma U
IU
Egbuniwe
St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine and NIHR Biomedical Research Centre at Guy's and St. Thomas's Hospitals and King's College London, London, United Kingdom.
Michiala J
MJ
Cafferkey
Department of Research Oncology, Division of Cancer Studies, King's College London, Guy's Hospital, London, United Kingdom.
James F
JF
Spicer
Clinical Oncology, Guy's and St. Thomas's NHS Foundation Trust, Guy's Hospital, London, United Kingdom.
Mark
M
Harries
St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine and NIHR Biomedical Research Centre at Guy's and St. Thomas's Hospitals and King's College London, London, United Kingdom.
Frank O
FO
Nestle
St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine and NIHR Biomedical Research Centre at Guy's and St. Thomas's Hospitals and King's College London, London, United Kingdom.
Katie E
KE
Lacy
St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine and NIHR Biomedical Research Centre at Guy's and St. Thomas's Hospitals and King's College London, London, United Kingdom. sophia.karagiannis@kcl.ac.uk.
Sophia N
SN
Karagiannis
D000818:Animals; D003131:Combined Modality Therapy; D004789:Enzyme Activation; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D058990:Molecular Targeted Therapy; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D057170:Translational Research, Biomedical; D019139:Tumor Escape
D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf