<b>Conclusion:</b> These results suggest that haspin can be considered as a viable anti-melanoma target, and that concomitant inhibition of haspin and MEK activities with small molecules could represent a novel therapeutic strategy with improved efficacy for treatment of melanoma.
<b>Purpose:</b> To examine the relationship between immune activity, PD-L1 expression, and tumor cell signaling, in metastatic melanomas prior to and during treatment with targeted MAPK inhibitors.<b>Experimental Design:</b> Thirty-eight tumors from 17 patients treated with BRAF inhibitor (<i>n</i> = 12) or combination BRAF/MEK inhibitors (<i>n</i> = 5) with known PD-L1 expression were analyzed.
Melanomas that contain B-RAF(V600E) mutations respond transiently to RAF and MEK inhibitors; however, resistance to these agents remains a formidable challenge.
Melanoma treatment has progressed in the past decade with the development and approval of immune checkpoint inhibitors targeting programmed death 1 (PD-1) or its ligand (PD-L1) and cytotoxic T lymphocyte-associated antigen 4, as well as small molecule inhibitors of BRAF and/or MEK for the subgroup of patients with BRAF<sup>V600</sup> mutations<sup>1-9</sup>.
Melanoma is a deadly tumor which in recent years has been successfully treated with immune checkpoint inhibitors as PD-1/PD-L1 and CTLA-4 inhibitors and targeted therapy as BRAF and MEK inhibitors.
MEK kinase inhibitors (trametinib and selumetinib) or kinase inhibitors directed against mutated BRAF(V600E) (vemurafenib and dabrafenib) have initial encouraging effects in the treatment of melanoma but acquired resistance appears almost invariably after some months.
MEK inhibitor therapy in combination with a BRAF inhibitor is more effective and less toxic than treatment with a BRAF inhibitor alone, and has become the standard of care for patients with BRAF-mutated melanoma.
A combined BRAF/MEK inhibitor regimen has been shown to lead to prolonged survival and progression-free survival in patients with metastatic BRAF V600-mutant melanoma.
A concomitant AURKA/BRAF and AURKA/MEK targeting overcame MAPK signaling activation-associated resistance signature in BRAF- and NRAS-mutated melanomas, respectively, and elicited heightened anti-proliferative activity and apoptotic cell death.
A SVM classifier built on this 7-pathway activation pattern correctly predicted the response of 10 BRAF-mutated melanoma cell lines to the MEK inhibitor AZD6244 in our experiments.
According to clinical trials, BRAF kinase inhibitors in combination with MEK kinase inhibitors are among the most promising chemotherapy regimens for the treatment of advanced BRAF-mutant melanoma, though the rate of BRAF mutation gene-bearing cutaneous melanoma is limited, especially in the Asian population.
Activated PI3K-AKT pathway may contribute to decrease sensitivity to inhibitors of key pathogenetic effectors (mutated BRAF, active NRAS or MEK) in melanoma.
Alterations in <i>MEK1/2</i> occur in cancers, both in the treatment-naïve state and following targeted therapies, most notably BRAF and MEK inhibitors in <i>BRAF</i>-V600E-mutant melanoma and colorectal cancer.
An UPLC-MS/MS method for the quantification of BRAF inhibitors (vemurafenib, dabrafenib) and MEK inhibitors (cobimetinib, trametinib, binimetinib) in human plasma. Application to treated melanoma patients.
Areas covered: In this non-systematic review, we report on the current knowledge on the use of SRS in combination with immunotherapy and BRAF/MEK inhibitors for patients with melanoma brain metastases, as well as ongoing trials in this field.
B-cell-derived IGF-1 is critical for resistance of melanomas to BRAF and MEK inhibitors due to emergence of heterogeneous subpopulations and activation of FGFR-3.
B-rapidly accelerated fibrosarcoma (BRAF) inhibitor encorafenib alone and in combination with MEK inhibitor binimetinib improves survival in BRAF-mutated melanoma patients.
Besides targeting B-Raf and MEK protein kinases, immunotherapies that include ipilimumab, pembrolizumab, and nivolumab have been FDA-approved for the treatment of melanomas.