Here, we explore whether BRAF/MEKi modulate rates of PD-1<sup>+</sup> melanoma cells, supporting an additional-lymphocyte-independent-basis for their therapeutic combination with anti-PD-1 antibody.<b>Experimental Design:</b> With data mining and flow cytometry, we assessed PD-1, PD-L1/2 expression on melanoma cell lines (CCLE, <i>N</i> = 61; validation cell lines, <i>N</i> = 7) and melanoma tumors (TCGA, <i>N</i> = 214).
PHIP-overexpressing melanomas include tumors with wild-type BRAF, neuroblastoma RAS viral (v-ras) oncogene homolog, and phosphatase and tensin homolog, demonstrating PHIP activation in triple-negative melanoma.
Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, can result in durable responses in patients with melanoma who have progressed after ipilimumab and BRAF inhibitors.
The use of selective BRAF inhibitors (BRAFi) has produced remarkable outcomes for patients with advanced cutaneous melanoma harboring a <i>BRAF<sup>V600E</sup></i> mutation.
To evaluate the existence of different molecular aberration patterns in melanoma associated with v-raf murine sarcoma viral oncogene homolog B1 (BRAF) or 9p21 locus alterations, eleven patient-derived melanoma cell lines were characterized.
Upregulation of MC1R expression was determined in BRAF<sup>V600E</sup> cells (A2058) and BRAF wild-type melanoma cells (MEWO) by quantitative real-time polymerase chain reaction, flow cytometry, and receptor-ligand binding assays.
Targeted therapy can successfully block oncogenic signaling in BRAF(V600)-mutant melanoma with high initial clinical responses, but relapse rates are also high.
Compared with chemotherapy, biochemotherapy (in this case, chemotherapy combined with both interferon-alpha and interleukin-2) and BRAF inhibitors improved progression-free survival; BRAF inhibitors (for BRAF-mutated melanoma) and anti-PD1 monoclonal antibodies improved overall survival.
Associations with the BRAF(T1799A) mutation (P<0.05) were as follows: low tumor thickness (odds ratio (OR)=3.3); low mitotic rate (OR=2.0); low Ki67 score (OR=5.0); low PH3 score (OR=3.3); superficial spreading melanoma (OR=10.0); pigmented melanoma (OR=3.7); a lack of history of solar keratoses (OR=2.7); a location on the trunk (OR=3.4) or extremity (OR=2.0); a high level of self-reported childhood sun exposure (OR=2.0); < or =50 years of age (OR=2.5); and fewer freckles (OR=2.5).
Overall, our findings show how upregulation of miR-204-5p and miR-211-5p following vemurafenib treatment enables the emergence of resistance, with potential implications for mechanism-based strategies to improve vemurafenib responses.<b>Significance:</b> Identification of miRNAs that enable resistance to BRAF inhibitors in melanoma suggests a mechanism-based strategy to limit resistance and improve clinical outcomes.<i></i>.
The BRAF mutation was frequently detected in patients with superficial spreading melanoma (OR=2·021; P<0·001) and in melanomas arising in nonchronic sun-damaged skin (OR=2·043; P=0·001).
This report presents a patient with HCL and malignant melanoma with the BRAFp.V600E mutation, and discusses the successful treatment of both cancers with the BRAF inhibitor dabrafenib.
In a large cohort of melanomas, 10 additional internal deletions were identified (0.4% of all melanomas; nine of which had concurrent BRAF mutations), as well as sporadically in other tumor types.
Here, we show intralesional molecular heterogeneity in a progressing V600EBRAF-mutant melanoma metastasis from a patient treated for 7 months with the BRAF inhibitor vemurafenib.
Potentially, BRAF mutation analysis of sentinel lymph node (SLN) biopsies could enhance the detection of micrometastases and improve the accuracy of nodal staging for patients with melanoma.
Acquisition of a BRAF mutation is not a founder event, but may be one of the multiple clonal events in melanoma development, which is selected for during the progression.
There is compelling evidence that oncogenic BRAF, in addition to driving melanoma proliferation, differentiation and survival, induces T-cell suppression directly through the secretion of inhibitory cytokines or through membrane expression of co-inhibitory molecules such as the PD-1 ligands PD-L1 or PD-L2.
In conclusion, our findings show miRNA dysregulation in malignant melanoma and its relation to established molecular backgrounds of BRAF and NRAS oncogenic mutations.