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Review
. 2017 Jun 16;8(43):75675-75686.
doi: 10.18632/oncotarget.18523. eCollection 2017 Sep 26.

Overcoming resistance to targeted therapy with immunotherapy and combination therapy for metastatic melanoma

Hilary R Keller  1   2   3   4 , Xin Zhang  4 , Li Li  4 , Helmut Schaider  5 , James W Wells  3
Affiliations
Review

Overcoming resistance to targeted therapy with immunotherapy and combination therapy for metastatic melanoma

Hilary R Keller (VSports app下载) et al. Oncotarget. .

Abstract

Resistance to targeted therapy is an ongoing problem for the successful treatment of Stage IV metastatic melanoma. For many patients, the use of targeted therapies, such as BRAF kinase inhibitors, were initially promising yet resistance inevitably occurred. Even after combining BRAF kinase inhibitors with MEK pathway inhibitors to offset re-activation of the MAP kinase pathway, resistance is still documented VSports手机版. Similarly, outcomes with immune checkpoint inhibitors as monotherapy were optimistic for some patients without relapse or progression, yet the majority of patients undergoing monotherapy have progressive disease. Will immunotherapy and combination therapy trials overcome resistance in metastatic melanoma. In an effort to treat resistant disease, new clinical trials evaluating the combination of immunotherapy with other therapies, such as kinase inhibitors, adoptive cell therapy, chimeric CD40 ligand to boost costimulation, or a tumor-specific oncolytic virus enhancing granulocyte macrophage colony-stimulating factor (GM-CSF) expression, are currently underway. Updated studies on the mechanisms of resistance, immune escape and options to reinvigorate immune cells support the continued discovery of new and improved forms of therapy. .

Keywords: immune inhibitory receptors; immunotherapy; metastatic melanoma; targeted therapy; therapy resistance V体育安卓版. .

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Conflict of interest statement

CONFLICTS OF INTEREST None.

Figures (V体育安卓版)

Figure 1
Figure 1. Targeted and immunotherapy against immune inhibitory receptors and resistance mechanisms
Immune inhibitory receptors and their ligands are paired as shown. Neurotrophins and nerve growth factors (NGF) bind to CD271 (p75NTR), whose expression can be induced under conditions of stress, resulting in downstream signaling pathways promoting survival, dedifferentiation, tumorigenesis, plasticity, metastasis, and the suppression of T cell activation. Transforming growth factor-α (TGFα), epidermal growth factor (EGF), and KIT ligand (stem cell factor or STEEL) can bind to a receptor tyrosine kinase (RTK), such as the EGF receptor (EGFR) or KIT receptor (c-KIT receptor or CD117). This promotes the activation of either the MAPK pathway or PI3K/AKT pathway. Kinase inhibitors can induce mutations in components of either pathway, as shown by green arrows. These induced mutations then promote the activation of downstream signaling, bypassing the targeted inhibition and resulting in the phosphorylation of microphthalmia-associated transcription factor (MITF). Expression of MITF leads to differentiation and pigmentation (via tyrosinase activity) as well as the proliferation and survival of melanocytes (through the upregulation of Bcl2). Activation of these pathways also promotes invasion and metastasis in melanoma tumor cells. Tim3 (HAVCR2) forms a heterodimer with CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule) inducing T cell inhibition, and also binds its ligand, Galectin 9 to then suppress T helper cell type 1 (Th1) function and induce cell death.
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