The Activation of MAPK in Melanoma Cells Resistant to BRAF Inhibition Promotes PD-L1 Expression That Is Reversible by MEK and PI3K Inhibition

Selective BRAF inhibition (BRAFi) provides a paradigm shift for melanoma treatment. The duration of benefit is typically limited before resistance develops. Interest remains in combining targeted and immune therapies to overcome resistance and improve durability of clinical benefit. One mechanism of...

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Bibliographic Details
Published in:Clinical cancer research 2013-02, Vol.19 (3), p.598-609
Main Authors: XIAOFENG JIANG, JUN ZHOU, GIOBBIE-HURDE, Anita, WARGO, Jennifer, STEPHEN HODI, F
Format: Article
Language:English
Subjects:
Antineoplastic agents
Apoptosis - drug effects
B7-H1 Antigen - genetics
B7-H1 Antigen - metabolism
Biological and medical sciences
Cell Line, Tumor
Dermatology
Drug Resistance, Neoplasm
Enzyme Activation
Gene Expression Regulation, Neoplastic
Humans
Medical sciences
Melanoma - genetics
Melanoma - metabolism
Mitogen-Activated Protein Kinase Kinases - metabolism
Models, Biological
Pharmacology. Drug treatments
Phosphatidylinositol 3-Kinases - metabolism
Protein Kinase Inhibitors - pharmacology
Proto-Oncogene Proteins B-raf - antagonists & inhibitors
Proto-Oncogene Proteins B-raf - metabolism
Proto-Oncogene Proteins c-jun - metabolism
Ribosomal Protein S6 Kinases - metabolism
Signal Transduction
STAT3 Transcription Factor - metabolism
TOR Serine-Threonine Kinases - metabolism
Tumors of the skin and soft tissue. Premalignant lesions
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Summary:Selective BRAF inhibition (BRAFi) provides a paradigm shift for melanoma treatment. The duration of benefit is typically limited before resistance develops. Interest remains in combining targeted and immune therapies to overcome resistance and improve durability of clinical benefit. One mechanism of evading immune destruction is programmed death-1-ligand 1 (PD-L1) expression by tumors that results in potent antitumor immune suppression. BRAFi-resistant melanoma cells were examined for changes in PD-L1 expression by immunoblot and flow cytometry. Signaling pathways involved in altering PD-L1 expression were examined. Strategies to maximize the effect of the BRAFi therapy were studied including MEKi, MEKi combinations, and additional pathways including phosphoinositide-3 kinase (PI3K). Melanoma cells resistant to BRAFi exhibit increased MAPK signaling and promotion of PD-L1 expression. PD-L1 expression is transcriptionally modulated by c-Jun and augmented by STAT3. MEK inhibition (MEKi) regains downregulation of MAPK signaling and suppresses the production of PD-L1. MEKi in melanoma cells shows dual therapeutic effects with simultaneous suppression of PD-L1 expression and induction of apoptosis. By combining MEKi with BRAFi, an additive effect on the inhibition of PD-L1 expression results. We report a novel mechanism that suppresses preexisting immune responses in patients with melanoma receiving BRAFi therapy. BRAFi resistance leads to increased expression of PD-L1 in melanoma cells, mediated by c-Jun and STAT3. MEKi may be feasible to counteract BRAFi resistance of MAPK reactivation and also for the additive effect of PD-L1 suppression. Potential therapeutic benefits of combining targeted inhibitors and immune modulation to improve patient outcomes should be investigated.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-12-2731